piperidines and Substance-Withdrawal-Syndrome

Cannabis has long been perceived as a drug causing questionable dependence. Only recently has a clinically recognized withdrawal syndrome been described, thus laying the foundations for specific treatment evaluations. Six different pharmacotherapies have been studied in cannabis withdrawal. Of these, only oral tetrahydrocannabinol, and perhaps mirtazapine, have shown some promise in the specific treatment of withdrawal symptoms. In cannabis dependence, rimonabant, and perhaps buspiron, have shown promising results. Clinical trials of oral tetrahydrocannabinol were less convincing. Cognitive and behavioral therapies and motivational enhancement therapies have proven their efficacy in several randomized controlled trials. Brief therapies have also been associated with good compliance and efficacy. Combinations with voucher incentives in certain populations have been associated with improved treatment compliance and reduced cannabis use. Only two studies have analyzed the cost-efficacy of psychotherapies. It would seem that brief combined cognitive and behavioral therapies, and motivational enhancement therapies are the most cost effective. For the moment, it is uncertain whether the additional treatment costs associated with voucher incentives are proportional to the accrued abstinence duration.

Topics: Behavior Therapy; Buspirone; Cannabinoids; Cognitive Behavioral Therapy; Combined Modality Therapy; Dronabinol; Humans; Marijuana Abuse; Mianserin; Mirtazapine; Motivation; Piperidines; Psychotherapy; Psychotropic Drugs; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Substance Withdrawal Syndrome

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

Topics: Antidepressive Agents; Aryl Hydrocarbon Hydroxylases; Clonidine; Cytochrome P-450 CYP2A6; Drug Delivery Systems; GABA Modulators; Humans; Narcotic Antagonists; Nicotine; Piperidines; Pyrazoles; Receptors, Nicotinic; Rimonabant; Substance Withdrawal Syndrome; Tobacco Use Disorder; Vaccination

Detoxification from drug abuse is strongly threatened by the occurrence of renewed episodes of drug intake. In human addicts, relapse to drug seeking may take place even after a considerably long period from the last drug consumption. Over the last decade, the endocannabinoid system has received remarkable attention due to its unique features, including its rewarding properties closely resembling those of the most commonly abused substances and its multiple therapeutic implications. Although limited at present, evidence is now emerging on a possible participation of the endogenous cannabinoid system in the regulation of relapsing phenomena. Both stimulation and blockade of the central cannabinoid CB-sub1 receptor have proved to play an important role in drug- as well as in cue-induced reinstatement of drug seeking behavior. Indeed, while CB-sub1 receptor stimulation may elicit relapse not only to cannabinoid seeking but also to cocaine, heroin, alcohol and methamphetamine, this effect is significantly attenuated, when not fully prevented, by pretreatment with the CB-sub1 receptor antagonist rimonabant. However, corroborating data on the involvement of the cannabinoid system in stress-induced reinstatement are still rather scarce. The present review attempts to collect data obtained from different laboratories using diverse experimental approaches, to provide a comprehensive picture of the recent evidence of a relationship between the cannabinoid system and the neurobiological mechanisms leading to relapse. For each class of abused drugs, the conspicuous progress made in delineating the role of the endocannabinoid system in relapse to drug seeking has been examined by placing particular emphasis on the findings obtained from behavioral studies. After summarizing findings and implications emerging from the reviewed studies, we conclude by briefly discussing what information is still missing and how missing information might be obtained.

Topics: Animals; Brain; Cannabinoid Receptor Modulators; Disease Models, Animal; Endocannabinoids; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reward; Rimonabant; Secondary Prevention; Substance Withdrawal Syndrome; Substance-Related Disorders

Cigarette smokers tend to die prematurely from a number of diseases. Cigarette smoking is an important modifiable risk factor for cardiovascular morbidity and mortality. Despite the clear health benefits of smoking cessation, smokers usually find it difficult to stop and behavioral therapies often prove insufficient. Pharmacologic intervention may aid the process because of the addictive nature of nicotine. Nicotine replacement therapy, which is regarded as first-line therapy, was developed to overcome the symptoms of nicotine withdrawal that many patients find distressing. Different modes of administration include inhalation and buccal or transdermal absorption. The orally administered non-nicotine drugs varenicline and bupropion are also regarded as first-line treatments, either used alone or as an adjunct to nicotine replacement therapy. Second-line treatments include clonidine and nortriptyline. Other treatment strategies that have been examined include monoamine oxidase inhibitors and selective serotonin reuptake inhibitors; efficacy has yet to be proven definitively. A novel approach to treatment using the cannabinoid-1 receptor antagonist rimonabant is also under investigation.

Topics: Administration, Cutaneous; Administration, Inhalation; Benzazepines; Bupropion; Chewing Gum; Clonidine; Coronary Artery Disease; Humans; Monoamine Oxidase Inhibitors; Nicotine; Nortriptyline; Piperidines; Pyrazoles; Quinoxalines; Receptors, Nicotinic; Rimonabant; Selective Serotonin Reuptake Inhibitors; Smoking; Smoking Cessation; Substance Withdrawal Syndrome; Tobacco Use Disorder; Tobacco, Smokeless; Varenicline

Remifentanil is a synthetic opioid derivate with an agonist activity at mu-opioid receptors. The pharmacokinetic profile differs from other synthetic opioids. Remifentanil is rapidly metabolised by unspecific blood and tissue esterases and the metabolites have almost no intrinsic activity. According to its unique pharmacokinetic profile, remifentanil-based anaesthesia might be associated with a high level of postoperative pain, therefore, an appropriate postoperative pain management is an import aspect. In addition, remifentanil withdrawal induces a compensatory up-regulation of secondary messenger pathways, inducing hyperalgesia. This review provides a comprehensive summary of basic and clinical research concerning the intraoperative use of remifentanil and postoperative pain therapy. The relative contribution of rapid degradation and withdrawal-induced hyperalgesia to postoperative pain will be discussed. In addition, this review attempts to identify potential clinical implications and treatment strategies.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Humans; Hyperalgesia; Pain, Postoperative; Piperidines; Remifentanil; Substance Withdrawal Syndrome

The use of marijuana for recreational and medicinal purposes has resulted in a large prevalence of chronic marijuana users. Consequences of chronic cannabinoid administration include profound behavioral tolerance and withdrawal symptoms upon drug cessation. A marijuana withdrawal syndrome is only recently gaining acceptance as being clinically significant. Similarly, laboratory animals exhibit both tolerance and dependence following chronic administration of cannabinoids. These animal models are being used to evaluate the high degree of plasticity that occurs at the molecular level in various brain regions following chronic cannabinoid exposure. In this review, we describe recent advances that have increased our understanding of the impact of chronic cannabinoid administration on cannabinoid receptors and their signal transduction pathways. Additionally, we discuss several potential pharmacotherapies that have been examined to treat marijuana dependence.

Topics: Animals; Cannabinoid Receptor Modulators; Cannabinoids; Drug Tolerance; Humans; Marijuana Abuse; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Substance Withdrawal Syndrome

Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates.. To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH.. 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments.. Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants.. Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.

Topics: Analgesia; Analgesics, Opioid; Drug Tolerance; Fentanyl; Gestational Age; Humans; Hyperalgesia; Hypnotics and Sedatives; Infant; Infant, Newborn; Infant, Newborn, Diseases; Intensive Care Units, Neonatal; Intensive Care Units, Pediatric; Piperidines; Remifentanil; Respiration, Artificial; Substance Withdrawal Syndrome

Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

Topics: Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Humans; Male; Marijuana Abuse; Mass Spectrometry; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome; Young Adult

Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the mu-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the alpha(2)-receptor agonist clonidine.. Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 microg x kg-1 x min-1 and S-ketamine at 5 microg x kg-1 x min-1 over a period of 30 min, respectively; clonidine infusion at 2 microg/kg for 5 min).. Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings.. Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

Topics: Adrenergic alpha-Agonists; Adult; Analgesics, Opioid; Anesthetics, Dissociative; Blood Pressure; Clonidine; Cross-Over Studies; Double-Blind Method; Electric Stimulation; Half-Life; Humans; Hyperalgesia; Infusions, Intravenous; Ketamine; Male; Oxygen; Pain Measurement; Physical Stimulation; Piperidines; Receptors, Opioid, mu; Remifentanil; Substance Withdrawal Syndrome

Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Excitatory Amino Acid Antagonists; Hot Temperature; Humans; Hyperalgesia; Ketamine; Pain; Physical Stimulation; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Remifentanil; Substance Withdrawal Syndrome

Chronic migraine (CM) patients frequently overuse symptomatic medications (SM). These medications may create a cycle of rebound, worsening of headache and withdrawal symptoms that perpetuate the headache itself. In addition, the overuse of such substances is believed to counteract the efficacy of preventive treatments. We conducted a prospective randomized open-label trial comparing approaches to out-patient management in 150 CM patients (125 women, 25 men; ages 18-80 years, mean 40.3 +/- 13.8) with overuse of SM. In each group, 50 patients received education and orientation and were then abruptly withdrawn from all SM. Immediately following withdrawal, the first group took prednisone (60 mg/ day 2 days, 40 mg/day 2 days and 20 mg/day 2 days) for 6 days, the second group did not have any regular medications to take and the third group took naratriptan (2.5 mg twice a day) during this initial period. All patients had similar profiles of headache characteristics and consumption (quality and quantity) of SM before initiation of the treatment, but most were not severe headache sufferers, heavy SM overusers or were overusing opioids. After 5 weeks the headache frequency and intensity, the prevalence and frequency of withdrawal symptoms and consumption of rescue medications during the first 6 days were compared between groups. In addition, adherence to treatment (who returned or not and for which reasons, between groups) and headache frequency, week by week, among the groups of patients were also compared. Forty-four (88%) patients from the prednisone group, 41 (82%) from the 'nothing' group and 35 (70%) from the naratriptan group adhered to the treatment and returned. The were no differences between groups with regard to treatment adherence (P = 0.072), headache frequency as well as intensity (P = 0.311) and decreasing of days with headache after 5 weeks and weekly (P = 0.275). However, the incidence of withdrawal symptoms and consumption of rescue drugs was higher among the patients who did not take regular medications during the first 6 days (P = 0.0001 and P = 0.006). We concluded that CM patients with moderate overuse of SM other than opioids may be detoxified on an out-patient basis regardless of the strategy adopted with regard to the use of regular drugs during the initial days of withdrawal, but prednisone and naratriptan may be useful for reducing withdrawal symptoms and rescue medication consumption. Further controlled studies are necessary to confir

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Chi-Square Distribution; Female; Headache Disorders; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Prednisone; Prospective Studies; Statistics, Nonparametric; Substance Withdrawal Syndrome; Tryptamines

Complete withdrawal from headache medication is the treatment of choice for medication-overuse headache. Discontinuation of the overused headache medication, however, results in the development of withdrawal headache, often associated with nausea, vomiting, and sleep disturbances.. In a prospective study of 95 patients, the authors investigated the duration and severity of withdrawal headache after overuse of various headache drugs, including single and combination analgesics, ergots, and triptans. All patients underwent standard inpatient withdrawal therapy for 14 days.. The duration of withdrawal headache was shorter in patients overusing triptans (4.1 days) than in patients overusing ergots (6.7 days) or analgesics (9.5 days; p < 0.002). The mean headache intensity on the first day of withdrawal did not differ between the groups (p = 0.821). By day 14, however, it was lower in patients overusing triptans (0.08) than in patients overusing ergots (0.4) or analgesics (0.9; p < 0.005). Rescue medication was requested less by patients undergoing triptan withdrawal (0.25 requests) than by patients undergoing ergot withdrawal (1.25) or analgesic withdrawal (1.85; p < 0.05). Similar to findings in the entire patient population, withdrawal headache was shorter and less severe in migraineurs overusing triptans than in those overusing ergots or analgesics. Because only patients with migraine, but no patient with tension-type headache, overused triptans, withdrawal headache was shorter in the group of patients with migraine alone (6.7 days versus 9.6 days for patients with tension-type headache and 8.5 days for patients with combination headache, p < 0.02).. The duration and severity of withdrawal clearly depend on the type of overused headache drug only.

Topics: Adult; Analgesics; Drug Therapy, Combination; Ergotamine; Female; Headache; Humans; Indoles; Male; Middle Aged; Oxazolidinones; Piperidines; Prospective Studies; Substance Withdrawal Syndrome; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

In a double-blind, 4 week study, 42 chronic schizophrenic inpatients receiving antipsychotic and antiparkinsonian (AP) drugs for greater than 3 months were either switched to placebo or maintained on biperiden. In the majority of the patients no clinically apparent discomfort was observed, and only two of 21 placebo patients developed extrapyramidal side effects (EPS) severe enough to require resumption of AP therapy. No significant increase was shown in most items on EPS. Our data suggest that for the majority of patients on long-term AP medication AP drugs should be prescribed only when EPS develop.

Topics: Adult; Aged; Antipsychotic Agents; Biperiden; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Schizophrenia; Substance Withdrawal Syndrome

The results of evaluating the therapeutic efficacy of the new psychotropic drugs adepren, didepil, anq tempalgin made by the "Farmakhim" plant (the People's Republic of Bulgaria) are presented. Clinical trials revealed new facts that allowed to expand the scope of the indications for use formulated in the "Farmakhim" recommendations. It was found that Adepren could be used with success (in addition to the indications suggested by "Farmakhim") in the treatment of patients with depressive-paranoid paroxysms of periodic schizophrenia taking its course in the presence of general depression, as well as patients with somatogenic lingering astheno-depressive states. The therapeutic efficacy of didepil (an antiepileptic) was found to be in a direct relationship with the disease duration, character of the attacks, presence or absence of epileptic chandes of personality. The effect was the best in cases of a short duration of the disease and absence of gross epileptic personality changes, when the paroxysmal disorders were confined mostly to grand mals. A new scheme for arresting the epileptic status with didepil solution is offered. For the first time the efficacy of tempalgin in the treatment of patients suffering from alcoholic abstinence syndrome was substantiated. Optimal doses of the drugs have been determined with regard to the disease nosology and the leading syndrome. Contraindications to the use of the drugs have also been formulated.

Topics: Adolescent; Adult; Aminopyrine; Aminoquinolines; Child; Clinical Trials as Topic; Depression; Dipyrone; Drug Combinations; Epilepsy; Female; Humans; Male; Mental Disorders; Middle Aged; Phenobarbital; Piperidines; Piperidones; Procyclidine; Psychotropic Drugs; Pyrrolidines; Substance Withdrawal Syndrome; Syndrome

Topics: Adult; Butyrophenones; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Middle Aged; Piperidines; Prolactin; Receptors, Dopamine; Schizophrenia; Substance Withdrawal Syndrome; Thiothixene; Tranquilizing Agents

Topics: Adult; Analysis of Variance; Basal Ganglia Diseases; Body Weight; Chlorpromazine; Chronic Disease; Clinical Trials as Topic; Electrocardiography; Electroencephalography; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Social Behavior; Substance Withdrawal Syndrome; Thioridazine; Toluene; Tranquilizing Agents; Vision Tests

Ethanol withdrawal commonly leads to anxiety-related disorder, a central factor toward negative reinforcement leading to relapse. The lateral habenula (LHb), an epithalamic nucleus, has emerged to be critical for both reward and aversion processing. Recent studies have also implicated the hyperactivity of LHb, adding to the emergence of negative emotional states during withdrawal from addictive drugs. Herein, we have studied the effects of glutamate transporter inhibitor (PDC), GluN2B-containing NMDAR antagonist (Ro25-6981), and intracellular calcium chelator (BAPTA-AM) injection in LHb on ethanol withdrawal symptoms. We found that ethanol 4 g/kg 20 % w/v intragastric (i.g.) for 10 days followed by 24 h of withdrawal showed a significant increase in somatic signs characterized by vocalization, shaking, and scratching. It also increased locomotor activity and anxiety-like behavior, collectively showing expression of ethanol withdrawal symptoms. The intra-LHb administration of PDC (0.5 ng) worsened the effect of ethanol withdrawal, whereas Ro25-6981 (2 and 4 ng) and BAPTA-AM (6.5 and 13 ng) significantly reversed ethanol withdrawal-induced behavior evident by a decrease in somatic signs, locomotor activity, and anxiety-like behavior. Further, pretreatment of Ro25-6981 and BAPTA-AM reduced the neuronal loss, whereas PDC increased it compared to the vehicle-treated group, as evidenced by NeuN staining. Altogether, our results suggest that increased glutamate, GluN2B activation, and likely calcium increase indicative of glutamate excitotoxicity-induced neuronal loss in LHb possibly endorse the emergence of ethanol withdrawal symptoms, while their inhibition might help in alleviating the ethanol withdrawal symptoms.

Topics: Alcoholism; Amino Acid Transport System X-AG; Animals; Anxiety; Ethanol; Glutamic Acid; Habenula; Male; Mice; Phenols; Piperidines; Substance Withdrawal Syndrome

Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads to alterations in MAPK signaling in NAc neurons, which facilitates changes in the glutamatergic system and thus behavioral changes. We have previously shown that following withdrawal from cocaine-induced behavioral sensitization (BS), an increase in glutamate receptor expression and elevated MAPK signaling was evident. Here, we set out to determine the time course and behavioral consequences of inhibition of extracellular signal-regulated kinase (ERK) or NMDA receptors following withdrawal from BS. We found that inhibiting ERK by microinjection of U0126 into the NAc at 1 or 6 days following withdrawal from BS did not affect the expression of BS when challenged with cocaine at 14 days. However, inhibition of ERK 1 day before the cocaine challenge abolished the expression of BS. We also inhibited NR2B-containing NMDA receptors in the NAc by microinjection of ifenprodil into the NAc following withdrawal from BS, which had no effect on the expression of BS. However, microinjection of ifenprodil to the NAc 1 day before challenge attenuated the expression of BS similar to ERK inhibition. These results suggest that following a prolonged period of withdrawal, NR2B-containing NMDA receptors and ERK activity play a critical role in the expression of cocaine behavioral sensitization.

Topics: Animals; Behavior, Animal; Cocaine; Excitatory Amino Acid Antagonists; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Nucleus Accumbens; Piperidines; Protein Kinase Inhibitors; Rats; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract.. TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist).. The inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR.. The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs.

Topics: Analgesics, Opioid; Animals; Cannabinoids; Diterpenes, Clerodane; Drug Tolerance; Ileum; Male; Mice; Mice, Inbred BALB C; Morphine; Muscle, Smooth; Naloxone; Piperidines; Pyrazoles; Receptors, Cannabinoid; Substance Withdrawal Syndrome

Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (-)-OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self-administration, alcohol withdrawal symptoms and cue-induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162's effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five-choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162-testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162's effects on the alcohol deprivation effect in long-term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre-treatment significantly improved motor impulsivity in the five-choice serial reaction time task in both alcohol and alcohol-naïve rats. Moreover, OSU6162 (30 mg/kg) pre-treatment prevented the alcohol deprivation effect, i.e. relapse-like drinking behavior after a forced period of abstinence in long-term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162's ability to attenuate alcohol-mediated behaviors.

Topics: Alcohol Abstinence; Alcoholism; Animals; Central Nervous System Depressants; Conditioning, Operant; Craving; Dopamine Agents; Dopaminergic Neurons; Ethanol; Impulsive Behavior; Male; Piperidines; Rats, Wistar; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Benzamides; Disease Progression; Drug Resistance; Female; Humans; Lymphoma, Follicular; Male; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazines; Pyrazoles; Pyrimidines; Retrospective Studies; Substance Withdrawal Syndrome; Treatment Outcome

Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation of one type results in the activation of the other. We examined whether (S)-(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl (ADX-47273), a positive allosteric modulator (PAM) of mGlu5 receptor, attenuates deficits in reversal learning induced by withdrawal (11-13days) from 'binge-like' ethanol input (5.0g/kg, i.g. for 5days) in the Barnes maze (a spatial learning) task in rats. We additionally examined the effects of ADX-47273 on the expression of the NMDA receptors subunit, GluN2B, in the hippocampus and prefrontal cortex, on the 13th day of ethanol withdrawal. Herein, withdrawal from repeated ethanol administration impaired reversal learning, but not the probe trial. Moreover, ADX-47273 (30mg/kg, i.p.) given prior to the first reversal learning trial for 3days in the Barnes maze, significantly enhanced performance in the ethanol-treated group. The 13th day of ethanol abstinence decreased the expression of the GluN2B subunit in the selected brain regions, but ADX-47273 administration increased it. In conclusion, positive allosteric modulation of mGlu5 receptors recovered spatial reversal learning impairment induced by withdrawal from 'binge-like' ethanol exposure. Such effect seems to be correlated with the mGlu5 receptors mediated potentiation of GluN2B-NMDA receptor mediated responses in the hippocampus and prefrontal cortex. Thus, our results emphasize the role of mGlu5 receptor PAM in the adaptive learning impaired by ethanol exposure.

Topics: Allosteric Regulation; Animals; Cognition; Ethanol; Male; Motor Activity; Oxadiazoles; Piperidines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Reversal Learning; Spatial Learning; Substance Withdrawal Syndrome

Topics: Adenine; Antineoplastic Agents; Biomarkers; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Substance Withdrawal Syndrome; Waldenstrom Macroglobulinemia; Withholding Treatment

Dopamine neurons in the ventral tegmental area (VTA) influence learned behaviors and neuropsychiatric diseases including addiction. The stress peptide corticotrophin-releasing factor (CRF) contributes to relapse to drug and alcohol seeking following withdrawal, although the cellular actions are poorly understood. In this study, we show that presynaptic CRF type 1 receptors (CRF-R1) potentiate GABA release onto mouse VTA dopamine neurons via a PKC-Ca

Topics: Alcoholism; Animals; Benzoxazines; Central Nervous System Depressants; Corticotropin-Releasing Hormone; Dopaminergic Neurons; Egtazic Acid; Ethanol; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred C57BL; Morpholines; Naphthalenes; Neuronal Plasticity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Corticotropin-Releasing Hormone; Receptors, Presynaptic; Substance Withdrawal Syndrome; Ventral Tegmental Area

A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence.. Precipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24-48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors.. Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.

Topics: Animals; Behavior, Animal; Benzodioxoles; Cannabinoid Receptor Agonists; Dronabinol; Indoles; Male; Marijuana Abuse; Mice; Mice, Inbred C57BL; Naphthalenes; Piperidines; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome

Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans.. We investigated in mice the role of CB. Memory impairment during nicotine withdrawal was blocked by the CB. These findings underline the interest of CB

Topics: Animals; Arachidonic Acids; Brain; Cannabinoid Receptor Antagonists; Endocannabinoids; GABAergic Neurons; Glycerides; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Nicotine; Piperidines; Polyunsaturated Alkamides; Pyramidal Cells; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, GABA; Recognition, Psychology; Rimonabant; Substance Withdrawal Syndrome

Glutamatergic projections to nucleus accumbens (NAc) drive drug-seeking behaviors during opioids withdrawal. Modulating glutamatergic neurotransmission provides a novel pharmacotherapeutic avenue for treatment of opioids dependence. Great deals of researches have verified that transient receptor potential vanilloid 1 (TRPV1) channels alters synaptic transmitter release and regulate neural plasticity. In the present study, whole-cell patch clamp recordings were adopted to examine the activity of TRPV1 Channels in regulating glutamate-mediated excitatory postsynaptic currents (EPSCs) in NAc of rat during morphine withdrawal for 3days and 3weeks. The data showed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and the amplitudes of evoked excitatory postsynaptic currents (eEPSCs) were increased during morphine withdrawal after applied with capsaicin (TRPV1 agonist). Capsaicin decreased the paired pulse ratio (PPR) and increased sEPSCs frequency but not their amplitudes suggesting a presynaptic locus of action during morphine withdrawal. All these effects were fully blocked by the TRPV1 antagonist Capsazepine. Additionally, In the presence of AM251 (CB1 receptor antagonist), depolarization-induced release of endogenous cannabinoids activated TRPV1 channels to enhance glutamatergic neurotransmission during morphine withdrawal. The functional enhancement of TRPV1 Channels in facilitating glutamatergic transmission was not recorded in dorsal striatum. Our findings demonstrate the ability of TRPV1 in regulating excitatory glutamatergic transmission is enhanced during morphine withdrawal in NAc, which would deepen our understanding of glutamatergic modulation during opioids withdrawal.

Topics: Animals; Capsaicin; Corpus Striatum; Excitatory Postsynaptic Potentials; Glutamic Acid; Male; Morphine; Narcotics; Neuronal Plasticity; Neurotransmitter Agents; Nucleus Accumbens; Piperidines; Presynaptic Terminals; Pyrazoles; Random Allocation; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome; Synaptic Transmission; Tissue Culture Techniques; TRPV Cation Channels

Topics: Adult; Anesthetics, Dissociative; Bipolar Disorder; Comorbidity; Drug and Narcotic Control; France; Humans; Male; Piperidines; Substance Withdrawal Syndrome; Substance-Related Disorders; Young Adult

Remifentanil is a kind of synthetic opioid which has gained wide clinical acceptance by anesthesiologists. In this study, we attempted to test whether withdrawal effects on learning mechanisms can be triggered by repeated low-dose remifentanil treatment. Male Sprague-Dawley (SD) rats were subjected to remifentanil (50μg/kgs.c.) twice per day at 12h intervals for 15 days. When the animals of remifentanil group were withdrawn from remifentanil at 10h after the last injection, changes in open field test, Morris water maze test (MWM) and synaptic efficacy were examined in each group. We demonstrated that repeated exposure to 50μg/kg remifentanil produced enhanced locomotor activity indicating that a remifentanil addiction animal model in rats was established. MWM results showed that exposure to remifentanil had no influence on the spatial cognition. After withdrawal of remifentanil rats showed impaired spatial cognition. In electrophysiology test, remifentanil group rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Immunohistochemistry results demonstrated increased NR2A/NR2B ratio that should be included depression of LTP. In the whole-cell patch-clamp recording, after elimination from remifentanil incubation, mEPSC frequency was down regulated in hippocampal CA1 neurons, indicating that basal synaptic transmission were affected by remifentanil withdrawal. Taken together, the current findings demonstrate that the remifentanil withdrawn rats exhibit obvious impairment of hippocampus-dependent memory and synaptic plasticity. Increased hippocampal NR2A/NR2B expression ratio and the changes of basal synaptic transmission may participate in the impairment of LTP.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Electric Stimulation; Exploratory Behavior; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Male; Maze Learning; Mental Recall; Neuronal Plasticity; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Remifentanil; Substance Withdrawal Syndrome; Synapses

Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self-administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A-containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25-6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cocaine-Related Disorders; Glutamic Acid; Male; MAP Kinase Signaling System; Microinjections; Phenols; Piperidines; Prefrontal Cortex; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Self Administration; Substance Withdrawal Syndrome; Sulfonamides; Synaptic Transmission

Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.. To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets.. BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans.. Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.

Topics: Animals; Benzodioxoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Nicotine; Piperidines; RNA, Messenger; Substance Withdrawal Syndrome

Inhibition of endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) reduces somatic morphine withdrawal signs, but its effects on aversive aspects of withdrawal are unknown. The present study investigated whether Δ(9)-tetrahydrocannabinol (THC), the MAGL inhibitor JZL184, the FAAH inhibitor PF-3845, or the dual FAAH/MAGL inhibitor SA-57 would reduce acquisition of morphine withdrawal-induced conditioned place avoidance (CPA) and jumping.. Mice were implanted with placebo or 75 mg morphine pellets, 48 h later injected with naloxone or saline and placed in the conditioning apparatus, and assessed for CPA at 72 h. Subjects were also observed for jumping behavior following naloxone challenge.. Naloxone (0.056 mg/kg) produced robust CPA in morphine-pelleted, but not placebo-pelleted, mice. Morphine pretreatment prevented the occurrence of withdrawal CPA and withdrawal jumping, while clonidine (an α2 adrenergic receptor agonist) only blocked withdrawal CPA. THC, JZL184, and SA-57 significantly reduced the percentage of mice that jumped during the conditioning session, but did not affect acquisition of withdrawal CPA. PF-3845 did not reduce morphine withdrawal CPA or jumping. Finally, neither THC nor the endocannabinoid catabolic enzyme inhibitors in non-dependent mice elicited a conditioned place preference or aversion.. These findings suggest that inhibiting endocannabinoid catabolic enzymes reduces somatic morphine withdrawal signs, but not aversive aspects as inferred in the CPA paradigm. The observation that non-dependent mice administered inhibitors of endocannabinoid degradation did not display place preferences is consistent with the idea that that endocannabinoid catabolic enzymes might be targeted therapeutically, with reduced risk of abuse.

Topics: Acetamides; Amidohydrolases; Animals; Avoidance Learning; Benzodioxoles; Carbamates; Conditioning, Psychological; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Monoacylglycerol Lipases; Morphine; Naloxone; Piperidines; Pyridines; Substance Withdrawal Syndrome

The glutamate N-methyl-d-aspartate (NMDA) receptor NR2B subunits are sensitive to ethanol and are found in brain areas related to ethanol addiction, dependence, development of alcohol tolerance, and alcohol withdrawal syndrome. Previous studies indicate that early-onset Cloninger type 2 alcoholics have an intact, responsive, dopaminergic system in the nucleus accumbens (NAC), whereas type 1 alcoholics have dopaminergic defects. NR2B-containing NMDA receptors in the NAC are involved in both non-opioid and opioid receptor-mediated reward. Our aim was to evaluate the putative [(3)H]ifenprodil binding alterations of NR2B receptors in limbic, hippocampal, and cortical brain areas of type 1 alcoholics (n=8), type 2 alcoholics (n=8), and control subjects (n=10) by postmortem whole hemisphere autoradiography. We found significantly different binding levels among these three subject groups, and the main difference was localized in the decreased binding in type 2 alcoholics and controls in the nucleus accumbens. Although preliminary and from relatively small diagnostic groups, these results suggest pathological alterations in the NR2B-mediated reward system of type 2 alcoholics.

Topics: Adolescent; Adult; Aged; Alcoholics; Alcoholism; Autoradiography; Brain; Female; Humans; Male; Middle Aged; Nucleus Accumbens; Piperidines; Protein Binding; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Young Adult

Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation, neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal.. The objective of this study is to introduce an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints.. The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test, and temperature), with some comparisons made to Δ(9)-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545.. In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC.. These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545.

Topics: Animals; Body Temperature; Cannabinoid Receptor Antagonists; Cannabinoids; Disease Models, Animal; Dronabinol; Drug Tolerance; Male; Mice; Morpholines; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome

Withdrawal from chronic nicotine is associated with cognitive deficits. Therapies that ameliorate cognitive deficits during withdrawal aid in preventing relapse during quit attempts. Withdrawal-induced deficits in contextual learning are associated with nicotinic acetylcholine receptor upregulation. The aim of the present study was to determine if the acetylcholinesterase inhibitor donepezil has the ability to reverse nicotine withdrawal-induced deficits in contextual learning. Results demonstrated that low doses of donepezil, which do not enhance contextual learning or alter locomotor activity/anxiety-related behavior, can reverse nicotine withdrawal-induced deficits in contextual learning. Thus, donepezil may have therapeutic value for ameliorating cognitive deficits associated with nicotine withdrawal and for preventing relapse.

Topics: Animals; Cholinesterase Inhibitors; Conditioning, Psychological; Donepezil; Electroshock; Fear; Freezing Reaction, Cataleptic; Indans; Locomotion; Male; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Nootropic Agents; Piperidines; Substance Withdrawal Syndrome

The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 (≥16 mg/kg) for 6 days displayed decreased CB1 receptor density and function in the brain, as assessed in [(3)H]SR141716A binding and CP55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, respectively. In contrast, normal CB1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB1 receptor tachyphylaxis/tolerance or cannabinoid dependence.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Arachidonic Acids; Benzodioxoles; Brain Chemistry; Cyclohexanols; Diclofenac; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Endocannabinoids; Glycerides; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Stomach Ulcer; Substance Withdrawal Syndrome; Substance-Related Disorders

The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Benzamides; Central Nervous System; Dogs; Female; Gastrointestinal Tract; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Tropanes

Inhibition of the endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates naloxone-precipitated opioid withdrawal signs in mice via activation of CB1 receptors. Complete FAAH inhibition blocks only a subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy, but is accompanied with some cannabimimetic side effects. Thus, the primary objective of the present study was to determine whether combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid withdrawal. To test this hypothesis, we examined whether combined administration of high-dose of the FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-dependent mice, a model with greater face validity than precipitating withdrawal with μ-opioid receptor antagonists. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 as well as the dual inhibitor SA-57 reduced all abrupt withdrawal signs (ie, platform jumping, paw flutters, head shakes, diarrhea, and total body weight loss), but did not elicit any cannabimimetic side effects. In addition, JZL184 or PF-3845 blocked naloxone-precipitated hypersecretion in morphine-dependent small intestinal tissue. Collectively, these results are the first to show that endocannabinoid catabolic enzyme inhibitors reduce abrupt withdrawal in morpine-dependent mice and are effective in a novel in vitro model of opioid withdrawal. More generally, these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach for the treatment of opioid dependence.

Topics: Amidohydrolases; Animals; Benzodioxoles; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Monoacylglycerol Lipases; Morphine; Morphine Dependence; Piperidines; Substance Withdrawal Syndrome

The endocannabinoid (eCB) system is an important regulator of the stress response and mediates several stress-related behaviors, including anxiety. Despite anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), few data exist that address functional interactions between these systems. Accordingly, we examined the effects of the CB1 receptor antagonist, AM251, on behavioral anxiety induced by (1) exogenous CRF, and (2) withdrawal from chronic cocaine exposure (mediated by CRF). After behavioral testing, we collected blood and assessed plasma corticosterone levels. In Experiment 1, male Long-Evans rats were pretreated with AM251 (0, 10, 100, or 200 μg, i.c.v.), followed by CRF (0 or 0.5 μg, i.c.v.), before testing for anxiety-like behavior in the elevated plus maze (EPM). In Experiment 2, rats were exposed to cocaine (20 mg/kg, i.p.) or saline for 14 consecutive days. Forty-eight hours following cocaine exposure, rats were pretreated with AM251 (0, 10, or 100 μg, i.c.v.) and tested in the EPM. AM251 produced an anxiogenic response at the highest dose, but reversed the behavioral anxiety induced by CRF and withdrawal from chronic cocaine in a dose-dependent manner. AM251 also increased plasma corticosterone levels, but did so irrespective of CRF treatment or cocaine preexposure. Our findings suggest that the anxiogenic effects of CRF and cocaine withdrawal are mediated, at least in part, by CB1 receptor transmission, and provide evidence in support of eCB-CRF interactions that are independent of the hypothalamic-pituitary-adrenal axis.

Topics: Animals; Anxiety; Behavior, Animal; Cocaine; Corticosterone; Corticotropin-Releasing Hormone; Dopamine Uptake Inhibitors; Hypothalamo-Hypophyseal System; Male; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

Recently, nuclear factor kappa B is indicated in the precipitation of opioid withdrawal syndrome. NF-κB activation is noted to control the transcription and biochemical activation of chemokines. Opioid receptor activation-linked chemokine stimulation is reported to mediate certain effects produced by prolonged opioid treatment. Ammonium pyrrolidine dithiocarbamate (APD) and RS 102895 are relatively selective inhibitors of NF-κB and C-C chemokine receptor 2, respectively.. The present study investigates the effect of APD and RS 102895 on morphine withdrawal signs in vitro and in vivo.. Morphine was administered twice daily for 5 days, following which a single day 6 injection of naloxone (8 mg/kg, i.p.) precipitated opioid withdrawal syndrome in mice. Withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and the frequency of jumping, rearing, fore paw licking and circling. Naloxone-induced contraction in morphine-withdrawn isolated rat ileum was employed as an in vitro model. An isobolographic study design was employed in the two models to assess potential synergistic activity between APD and RS 102895.. APD and RS 102895 dose-dependently attenuated naloxone-induced morphine withdrawal syndrome both in vivo and in vitro. APD was also observed to exert a synergistic interaction with RS 102895.. It is concluded that APD and RS 102895 attenuate morphine withdrawal signs possibly by a NF-κB and C-C chemokine receptor 2 activation pathway-linked mechanisms potentially in an interdependent manner.

Topics: Animals; Benzoxazines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Ileum; Male; Mice; Morphine; Naloxone; NF-kappa B; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, CCR2; Substance Withdrawal Syndrome; Thiocarbamates

Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n = 4) discriminating Δ⁹-tetrahydrocannabinol (Δ⁹-THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n = 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic Δ⁹-THC (1 mg/kg s.c. 12 h) treatment. Δ⁹-THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating Δ⁹-THC; the ED₅₀ values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32-3.2 mg/kg) produced surmountable antagonism of Δ⁹-THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA₂/pK(B) values of 6.65, 6.68, and 6.79 in the presence of Δ⁹-THC, JWH-018, and JWH-073, respectively. In Δ⁹-THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED₅₀ value of rimonabant was 0.20 mg/kg. Δ⁹-THC (1-10 mg/kg), JWH-018 (0.32-3.2 mg/kg), and JWH-073 (3.2-32 mg/kg) dose-dependently attenuated the rimonabant-discriminative stimulus (i.e., withdrawal). These results suggest that Δ⁹-THC, JWH-018, and JWH-073 act through the same receptors to produce Δ⁹-THC-like subjective effects and attenuate Δ⁹-THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulus-outcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than Δ⁹-THC.

Topics: Animals; Behavior, Animal; Conditioning, Operant; Data Interpretation, Statistical; Discrimination Learning; Discrimination, Psychological; Dose-Response Relationship, Drug; Dronabinol; Female; Hallucinogens; Illicit Drugs; Indoles; Macaca mulatta; Male; Marijuana Abuse; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome

We describe a 62-year-old female diagnosed with Alzheimer's disease, who had been treated with donepezil for approximately 1 year. When she developed a low-grade fever and digestive complaints, her family physician interpreted these symptoms as side effects of the drug and ordered donepezil to be discontinued. Not only was there no improvement of the somatic symptoms after discontinuation of donepezil, but there was also a worsening of the dementia symptoms, culminating in delirium. When donepezil was re-prescribed, the delirium resolved and the patient's mental state stabilized. The authors urge great caution in discontinuing treatment with acetylcholinesterase inhibitors such as donepezil.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Delirium; Dementia; Donepezil; Female; Humans; Indans; Middle Aged; Piperidines; Substance Withdrawal Syndrome; Withholding Treatment

The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety ('hangover anxiety'). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism.

Topics: Alcoholism; Animals; Anxiety; Central Nervous System Depressants; Conditioning, Operant; Cues; Dynorphins; Ethanol; Male; Narcotic Antagonists; Piperidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Recurrence; Stress, Psychological; Substance Withdrawal Syndrome; Tetrahydroisoquinolines

Topics: Animals; Awards and Prizes; Cognition Disorders; Cyclooxygenase Inhibitors; Diclofenac; Male; Methamphetamine; Mice; Mice, Inbred ICR; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

New medications for alcohol use disorder (AUD) are needed. Long-term alcohol consumption leads to a dysregulated dopamine system. A novel approach to normalize these dysregulations might be treatment with "monoamine stabilizers," a novel class of compounds characterized by the ability to either suppress, stimulate, or not influence dopamine activity depending on the prevailing dopaminergic tone.. The effects of the monoamine stabilizer (-)-OSU6162 (OSU6162) on voluntary ethanol intake and ethanol withdrawal symptoms were evaluated in rats voluntarily consuming ethanol for at least 3 months before testing. Furthermore, effects of OSU6162 on ethanol seeking behavior were evaluated with the progressive ratio and cue-induced reinstatement paradigms. Finally, the interaction of OSU6162 with ethanol on dopamine output and metabolism was studied with microdialysis.. The OSU6162 attenuated several ethanol-mediated behaviors, including voluntary ethanol consumption, ethanol withdrawal symptoms, operant ethanol self-administration under progressive ratio schedule, and cue-induced reinstatement of ethanol seeking in rats that had voluntarily consumed ethanol for at least 3 months before treatment. In addition, OSU6162 blunted ethanol-induced dopamine output in nucleus accumbens of ethanol-naïve rats.. These results highlight the ability of OSU6162 to stabilize dopamine activity depending on the prevailing dopaminergic tone and indicate that OSU6162 might decrease ethanol intake by attenuating the acute rewarding properties of ethanol. In addition, OSU6162 might have potential to prevent relapse triggered by alcohol craving, alcohol related cues, and or an urge to relieve abstinence symptoms. The present study is to our knowledge the first indicating that OSU6162 might serve as a novel medication for AUD.

Topics: Alcohol Drinking; Animals; Behavioral Symptoms; Cues; Disease Models, Animal; Dopamine; Drug Discovery; Ethanol; Male; Microdialysis; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Piperidines; Rats; Reward; Secondary Prevention; Substance Withdrawal Syndrome

A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.

Topics: Aging; Amygdala; Animals; Anxiety; Brain-Derived Neurotrophic Factor; Corticotropin-Releasing Hormone; Exploratory Behavior; In Situ Hybridization; Interpersonal Relations; Male; Microfilament Proteins; Motor Activity; Nerve Tissue Proteins; Neuronal Plasticity; Neuropeptide Y; Neuropeptides; Nicotine; Nicotinic Agonists; Phenotype; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

Early treatment discontinuation will have a negative effect on a drug's benefit-risk profile if discontinuation occurs earlier in time than the positive effects of treatment. This non-persistence of therapy has been associated with an increased risk of adverse health outcomes.. The aim of this study was to explore relationships between patient characteristics and reasons for and time to discontinuation of rimonabant therapy, focusing on psychiatric events, because these were the main safety concerns for rimonabant.. A modified prescription-event monitoring (M-PEM) study was conducted for rimonabant. Descriptive statistics were used to describe the patient population. Rate ratios with 95% confidence intervals (CIs) were calculated to explore associations between patient characteristics and selected categories of reasons for stopping (RfS). Median times to discontinuation were compared using the Mann-Whitney U test.. The cohort comprised 10,011 users of rimonabant, three of which were excluded from this analysis because of missing age or sex. A total of 7204 patients (72.0%) stopped using rimonabant (median observation time 323 days, interquartile range: 279-371 days). In addition, patients with a history of psychiatric illness were more likely to discontinue rimonabant therapy early for all reasons, but most pronounced due to psychiatric events (rate ratio 1.79; 95% CI 1.54, 2.09) than those without a history of psychiatric illness. In contrast, the rates of discontinuation due to lack of effectiveness, any clinical events and psychiatric events in patients with cardiovascular disease, type 2 diabetes mellitus, dyslipidaemia or hypertension tended to be lower (not all being significant) than those without. For patients who discontinued treatment due to lack of effectiveness, the median time to discontinuation was significantly shorter for patients with a history of psychiatric illness, compared with patients without a history of psychiatric illness (86 vs 97 days, p = 0.03). For patients discontinuing treatment due to psychiatric events, the difference in median time to discontinuation was also 11 days (64 vs 75 days, p = 0.38), although not statistically significant. For patients stopping due to any clinical event, median time to discontinuation was comparable for patients with and without a history of psychiatric illness (61 vs 63 days, p = 0.90).. In this study, reasons for and time to discontinuation were associated with patient characteristics such as medical history. Patients discontinued treatment because of psychiatric events early after starting. In general, identification and characterization of early discontinuers, and increasing the understanding of reasons for stopping, may help healthcare professionals to develop targeted interventions to further improve treatment compliance, thereby optimizing treatment benefits and drug safety.

Topics: Adult; Body Mass Index; Cannabinoid Receptor Antagonists; Cohort Studies; Drug Monitoring; Drug Prescriptions; Female; Humans; Male; Mental Disorders; Middle Aged; Obesity; Patient Compliance; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Substance Withdrawal Syndrome; Time Factors

Endocannabinoid and serotonin systems are implicated in mechanisms underlying depression-like symptoms. Involvement of serotonin in mood disorders occurring after smoking cessation has been observed. We studied the interactions between endocannabinoid and serotonergic systems in mood and behavioral disorders caused by nicotine cessation. The effects of the endocannabinoid transport inhibitor AM404 and the cannabinoid receptor 1 antagonist AM251 in a nicotine-dependent rodent model were investigated.. Dependence was induced by subcutaneous injections of nicotine (2 mg/kg, 4 injections daily) for 15 consecutive days in mice. Animals treated with AM404 or AM251 were tested for locomotor activity and abstinence signs 24 hr after nicotine withdrawal and in forced swimming test (FST) at different times: immediately after last nicotine injection (t = 0) and 15 and 30 days after nicotine withdrawal. In nicotine-dependent mice treated with AM404 or AM251, expression of diencephalic serotonin receptor 1(A) (5-HT1(A)) was also measured. Effects of AM404, AM251, and WAY 100635 (5-HT(1A) receptor antagonist) in mice subjected to FST were evaluated.. A decrease in diencephalic 5-HT(1A) levels was observed in mice previously injected with nicotine. In the same animals, AM251 caused (0.5-2 mg/kg) a significant decrease of abstinence signs and AM404 (0.5-2 mg/kg) provoked a significant dose-dependent reduction in immobility time in the FST. Either AM251 or WAY 100635 antagonized anti-immobility effects of AM404.. Data indicate the existence of a link between serotonergic and endocannabinoid systems in the mechanisms underlying mood disorders caused by nicotine abstinence and suggest that these interactions are potential targets for pharmacological aid in smoking cessation.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Cannabinoid Receptor Modulators; Disease Models, Animal; Drug Interactions; Endocannabinoids; Male; Mice; Mood Disorders; Motor Activity; Nicotine; Piperazines; Piperidines; Pyrazoles; Pyridines; Random Allocation; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Smoking Cessation; Substance Withdrawal Syndrome

Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self-administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs.

Topics: Analgesics, Opioid; Animals; Choice Behavior; Cocaine; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Female; Infusions, Intravenous; Macaca mulatta; Male; Morphine; Morphine Dependence; Motivation; Piperidines; Remifentanil; Substance Withdrawal Syndrome

Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis.. Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice.. Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes.. The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.

Topics: Animals; Dose-Response Relationship, Drug; Dronabinol; Male; Marijuana Abuse; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Piperidines; Pyrazoles; Rimonabant; Spatial Behavior; Substance Withdrawal Syndrome

In this study, the use-dependent, nicotinic receptor antagonist bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24 h basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction.

Topics: Animals; Behavior, Addictive; Decanoic Acids; Disease Models, Animal; Male; Morphine; Morphine Dependence; Nicotinic Antagonists; Piperidines; Rats; Rats, Wistar; Self Administration; Substance Withdrawal Syndrome

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acid; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cannabinoid Receptor Modulators; Diarrhea; Dronabinol; Electric Stimulation; Endocannabinoids; Hydrolysis; Ileum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Piperidines; Prostaglandins; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance Withdrawal Syndrome; Weight Loss

Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

Topics: Animals; Cannabinoids; Cell Death; Cells, Cultured; Ethanol; Excitatory Amino Acid Agonists; Mice; N-Methylaspartate; Neurons; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') abusers have persistent neuropsychiatric deficits including memory impairments after the cessation of abuse. On the other hand, cannabinoid CB(1) receptors have been implicated in learning/memory, and are highly expressed in the hippocampus, a region of the brain believed to have an important function in certain forms of learning and memory. In this study, we clarified the mechanism underlying the cognitive impairment that develops during MDMA withdrawal from the standpoint of the cannabinoid CB(1) receptors. Mice were administered MDMA (10 mg/kg, i.p.) once a day for 7 days. On the 7th day of withdrawal, a novel object recognition task was performed and the amount of cannabinoid CB(1) receptor protein was measured with western blotting. Recognition performance was impaired on the 7th day of withdrawal. This impairment was blocked by AM251, a cannabinoid CB(1) receptor antagonist, administered 30 min before the training trial or co-administered with MDMA. At this time, the level of cannabinoid CB(1) receptor protein increased significantly in the hippocampus but not the prefrontal cortex or striatum. This increase of CB(1) receptor protein in the hippocampus was also blocked by the co-administration of AM251. Furthermore, CB(1) receptor knockout mice showed no impairment of recognition performance on the withdrawal from MDMA. The impairment of recognition memory during withdrawal from MDMA may result from the activation of cannabinoid CB(1) receptors in the hippocampus.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Gene Expression Regulation; Hallucinogens; Hippocampus; Male; Memory Disorders; Mice; Mice, Knockout; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology; Substance Withdrawal Syndrome; Time Factors

The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure.. To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated.. Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control.. The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Blood Pressure; Bradycardia; Dogs; Dose-Response Relationship, Drug; Etorphine; Evoked Potentials, Somatosensory; Heart Rate; Hyperalgesia; Hypotension; Naloxone; Narcotic Antagonists; Piperidines; Remifentanil; Substance Withdrawal Syndrome; Sufentanil

In the present study, sexual behavior of male rats was assessed following prolonged treatment with the CB(1) receptor agonist, HU-210 (0.1mg/mg/day for 10 days) under conditions of drug maintenance, spontaneous withdrawal and precipitated withdrawal (induced via administration of the CB(1) receptor antagonist AM251; 1mg/kg). Following subchronic cannabinoid treatment, sexual activity in male rats was impaired under both the drug maintenance and spontaneous withdrawal conditions, as revealed by a reduction in frequency of both intromissions and ejaculations. Notably, the induction of precipitated drug withdrawal reversed the negative effects of subchronic HU-210 treatment on sexual activity as seen by a reversal of the suppression of ejaculations. These data illustrate that, contrary to expectations, the impairments in male sexual activity following protracted cannabinoid administration are not due to drug withdrawal, per se, but are likely mediated by neuroadaptive changes provoked by repeated drug exposure.

Topics: Animals; Copulation; Dose-Response Relationship, Drug; Dronabinol; Female; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

Withdrawal from cocaine use often is associated with anxiety and depressive states. In this study the use-dependent, nicotinic acetylcholine receptor antagonist bis-(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was studied for its ability to reduce these symptoms in two rat models of anxiety and depression. Rats were administered saline vehicle, or two escalating doses of cocaine, for a period of 5 days and they were evaluated during the period after cocaine discontinuation in the elevated plus maze (anxiety) and the forced swim test (affect). BTMPS (0.25, 0.5, or 0.75mg/kg) was co-administered with saline or cocaine in the dependence phase. Withdrawal from cocaine administration alone resulted in reductions in both the time spent in the open arms of the elevated plus maze test, as well as entries into, and out of, the open arms of the maze. Withdrawal from cocaine also resulted in a reduction of escape behaviors, and the time to first immobility, in the forced swim test. Treatment with BTMPS produced a reversal of cocaine-induced anxiety-like behaviors in the elevated plus maze, including an increase (up to 68%) in time spent in the open arms of the maze and an increase in the number of crossings between open and enclosed arms. BTMPS also reduced depressive-like behaviors associated with the forced swim test, including up to a 62% increase in the time to first immobility and a 50% increase in escape behavior. These results provide proof of concept for the development and use of cholinergic compounds in the treatment of substance abuse.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cocaine; Decanoic Acids; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Male; Maze Learning; Nicotinic Antagonists; Piperidines; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Swimming

Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking.. The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment.. JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine's antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs.. Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.

Topics: Analgesics; Animals; Anxiety; Buprenorphine; Dose-Response Relationship, Drug; Hyperalgesia; Hypothermia; Male; Mice; Morphine; Nicotine; Piperidines; Receptors, Opioid, kappa; Reward; Substance Withdrawal Syndrome; Tetrahydroisoquinolines

Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder. However, in contrast to humans, PCP and PCP withdrawal-induced memory deficits in rodents are reversed by antipsychotic drugs such as clozapine. One possible explanation is that the memory tasks used in animal studies do not simultaneously test the What? Where? When? components that characterize episodic memory in human tasks. We investigated whether subchronic PCP withdrawal disrupts memory in rats in a task that requires simultaneous integration of memory for object, place and context. Rats learn to discriminate objects under specific spatial and contextual conditions analogous to the What? Where? When? components of human episodic memory. We found that PCP withdrawal impaired performance on this task and that the atypical antipsychotic drug clozapine did not reverse this impairment. However the acetylcholinesterase inhibitor (AChEI) donepezil, which has been shown to improve episodic memory in humans did reverse the effect of PCP. This suggests that PCP withdrawal disruption of object-place-context recognition in rats may prove to be a useful model to investigate episodic memory impairment in schizophrenia and supports the suggestion that AChEIs could prove to be a useful pharmacological strategy to specifically treat episodic memory problems in schizophrenia.

Topics: Animals; Clozapine; Donepezil; Indans; Male; Memory Disorders; Memory, Episodic; Phencyclidine; Piperidines; Rats; Substance Withdrawal Syndrome

Marijuana discontinuation has been recently reported to be anxiogenic in humans, which may predict relapse. Limited animal research has been carried out to model this withdrawal-associated negative affect. The current study sought to investigate the potential anxiety-like effects of cannabinoid withdrawal in mice. Male ICR mice were injected s.c. with delta9-tetrahydrocannabinol (THC) at 10mg/kg or vehicle once daily for 10 days. To precipitate withdrawal, the cannabinoid CB1 antagonist SR141716 (0.3, 1.0, or 3.0mg/kg) or vehicle was administrated i.p. 4h following the last THC or vehicle treatment. Thirty minutes later, mice were tested on the elevated plus-maze (EPM) for 5min. SR141716 did not significantly change EPM behaviors in vehicle-treated mice. In contrast, SR141716 precipitated a reduction in exploration of the open arms of EPM in mice repeatedly treated with THC vs vehicle. At 3.0mg/kg, SR141716 significantly reduced % open arm entries of the total arm entries, % open arm time of total time in arms, and the absolute time spent in open arms. No significant differences in the number of closed or total arm entries were observed, indicating that the behavioral changes were not due to altered motor activity. Collectively, the present results constitute the first evidence that cannabinoid withdrawal produces anxiety-like effects in mice. This animal model may help to identify the mechanisms that contribute to adaptations in the neuronal circuitry of the brain that are expressed as emotional symptoms of cannabinoid withdrawal.

Topics: Animals; Anxiety; Dronabinol; Emotions; Male; Maze Learning; Mice; Mice, Inbred ICR; Piperidines; Psychotropic Drugs; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome

Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Delta(9)-tetrahydrocannabinol (Delta(9)-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Delta(9)-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED(50) = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Delta(9)-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Delta(9)-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Delta(9)-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the alpha(2)-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Delta(9)-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest that cannabinoid and noncannabinoid (alpha(2)-adrenergic) agonists are potentially useful therapeutics for marijuana dependence inasmuch as they attenuate the subjective experience of Delta(9)-THC withdrawal.

Topics: Adrenergic Agonists; Animals; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Clonidine; Cyclohexanols; Discrimination, Psychological; Dronabinol; Female; Heart Rate; Macaca mulatta; Male; Morpholines; Motor Activity; Naphthalenes; Piperidines; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome

Cannabinoid withdrawal produces a hypofunction of mesencephalic dopamine neurons that impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment with two structurally different cannabinoid agonists, Delta(9)-tetrahydrocannabinol and CP55 940 (CP) rats were withdrawn spontaneously and pharmacologically with the CB1 antagonist SR141716A (SR). In these two conditions, evaluation of tyrosine hydroxylase (TH)-positive neurons revealed significant morphometrical reductions in the ventrotegmental area but not substantia nigra pars compacta of withdrawn rats. Similarly, confocal analysis of Golgi-Cox-stained sections of the nucleus accumbens revealed a decrease in the shell, but not the core, of the spines' density of withdrawn rats. Administration of the CB1 antagonist SR to control rats, provoked structural abnormalities reminiscent of those observed in withdrawal conditions and support the regulatory role of cannabinoids in neurogenesis, axonal growth and synaptogenesis by acting as eu-proliferative signals through the CB1 receptors. Further, these measures were incorporated into a realistic computational model that predicts a strong reduction in the excitability of morphologically altered MSN, yielding a significant reduction in action potential output. These pieces of evidence support the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system and provide direct morphological evidence for functional abnormalities associated with cannabinoid dependence at the level of dopaminergic neurons and their postsynaptic counterpart and are coherent with recent hypothesis underscoring a hypodopaminergic state as a distinctive feature of the 'addicted brain'.

Topics: Animals; Axons; Cannabinoids; Dopamine; Limbic System; Male; Marijuana Abuse; Mesencephalon; Neural Pathways; Neurogenesis; Neuronal Plasticity; Neurons; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome; Substantia Nigra; Synapses; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Based on phenomenological similarities between anhedonia (reward deficits) associated with drug withdrawal and the negative symptoms of schizophrenia, we showed previously that the atypical antipsychotic clozapine attenuated reward deficits associated with psychostimulant withdrawal. Antagonism of alpha(2) adrenergic and 5-HT(2A) receptors may contribute to these effects of clozapine. We investigated here whether blockade of alpha(2) or 5-HT(2A) receptors by idazoxan and M100907, respectively, would reverse anhedonic aspects of psychostimulant withdrawal. Idazoxan treatment facilitated recovery from spontaneous nicotine, but not amphetamine, withdrawal by attenuating reward deficits and increase the number of somatic signs. Thus, alpha(2) adrenoceptor blockade may have beneficial effects against nicotine withdrawal and may be involved in the effects of clozapine previously observed. M100907 worsened the anhedonia associated with nicotine and amphetamine withdrawal, suggesting that monotherapy with M100907 may exacerbate the expression of the negative symptoms of schizophrenia or nicotine withdrawal symptoms in people, including schizophrenia patients, attempting to quit smoking.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic Uptake Inhibitors; Amphetamine; Animals; Brain; Dihydro-beta-Erythroidine; Electrodes, Implanted; Fluorobenzenes; Ganglionic Stimulants; Idazoxan; Male; Nicotine; Piperidines; Rats; Rats, Wistar; Receptors, Nicotinic; Reward; Serotonin Antagonists; Substance Withdrawal Syndrome

Opioid withdrawal increases the reinforcing effectiveness of the μ-opioid agonist remifentanil in rodents. The current study explored the selectivity of this effect by assessing operant behavior maintained by drug and non-drug reinforcers, remifentanil, cocaine, a palatable liquid food, and standard food pellets, as a function of opioid dependence and withdrawal.. Operant responding exhibited by nondependent, morphine-naïve groups was compared with responding exhibited by morphine-dependent and withdrawn groups. Dependence was established using a noncontingent morphine dosing procedure that has been previously verified to maintain dependence while allowing for daily behavioral observation during a withdrawn state. Behavior maintained by remifentanil (0.10-10.0 μg/kg/infusion), cocaine (0.032-1.0 mg/kg/infusion), a palatable liquid food reinforcer (3.2-100.0% Vanilla Ensure® and water), or food pellets was assessed in dependent and nondependent groups.. Morphine withdrawal enhanced remifentanil self-administration, resulting in an upward and rightward shift of the descending limb of the dose-response curve, and increased operant responding for both food reinforcers. However, opioid withdrawal did not affect cocaine self-administration, nor did it affect responding for water.. Enhanced operant responding observed under opioid-dependent and withdrawn conditions, while selective, is generalized to some nonopioid reinforcers.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Cocaine; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Morphine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Reinforcement Schedule; Remifentanil; Self Administration; Substance Withdrawal Syndrome

To investigate the respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome after sedation interruption.. Prospective, interventional, single-center study in 30 ventilated ICU patients.. Metabolic [oxygen consumption (VO(2)), CO(2) production (VCO(2)), resting energy expenditure (REE)], respiratory [minute ventilation (V (E)), tidal volume (V (T)), respiratory rate (RR)] and hemodynamic (HR, SAP, MAP) parameters were measured in 30 ventilated ICU patients. Measurements were performed first under sedation with remifentanil-propofol, then after sedation interruption, and finally after clonidine administration (0.9-1.8 mg of clonidine in two doses of 10 min interval).. Sedation interruption produced significant increases in the hemodynamic parameters (SAP and MAP by 33%, HR by 37%), and metabolic rate (increase in VO(2) by 70%, VCO(2) by 88% and REE by 74%), leading to high respiratory demands (increase in V (E) from 9 to 15 l/min). The V (E) was increased due to a twofold increase in the RR; V (T) remained constant. In 25 out of 30 patients, clonidine administration decreased the hemodynamic (SAP, MAP and HR), metabolic (VO(2), VCO(2), REE) and respiratory parameters to values close to those observed with sedation. Clonidine induced mild sedation and patients became more cooperative with the ventilator. All patients responding to clonidine were weaned from the ventilator in 2 days (median, range 1-18 days).. Patients with withdrawal syndrome had significantly elevated hemodynamic, metabolic and respiratory demands. Clonidine significantly decreased these demands, induced mild sedation and facilitated patient cooperation with the ventilator, enabling ventilator weaning.

Topics: Adrenergic alpha-Agonists; Adult; Calorimetry, Indirect; Carbon Dioxide; Clonidine; Electrocardiography; Energy Metabolism; Female; Hemodynamics; Humans; Hypertension; Hypnotics and Sedatives; Male; Oxygen Consumption; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration, Artificial; Respiratory Insufficiency; Rest; Substance Withdrawal Syndrome; Tachycardia; Ventilator Weaning

Research has shown that enhancement of cannabinoid CB(1) receptor activity elicits an antidepressant-like response in the forced swim test (FST); however, the effects of chronic administration of cannabinoid agents in the FST are not well characterized. In Experiment 1, the CB(1) receptor agonist HU-210 (0.1 mg/kg) was administered for 10 days to male rats, following which animals were exposed to the FST. In Experiment 2, the same protocol was utilized; however, prior to the FST animals were co-treated with either prazosin (1 mg/kg; an alpha(1)-adrenoreceptor antagonist) or propranolol (2.5 mg/kg; a beta-adrenoreceptor antagonist). In Experiment 3, the same protocol was employed in both male and female rats, and the role of drug withdrawal was examined by administration of the CB(1) receptor antagonist AM251 (1 mg/kg) prior to the FST. Experiment 1 revealed that HU-210 administration evoked a reduction in immobility and increase in struggling that was identical to that produced by the antidepressant desipramine (10 mg/kg). Experiment 2 revealed that this effect was attenuated by both alpha- and beta-adrenoreceptor antagonists, suggesting noradrenergic involvement in this antidepressant-like profile. Experiment 3 demonstrated that HU-210 administration produced an antidepressant response in both males and females, which was attenuated by the induction of precipitated withdrawal. These results show that protracted administration of a CB(1) receptor agonist produces an antidepressant-like response in the FST in both sexes, which appears to involve the noradrenergic system.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Behavior, Animal; Cannabinoids; Desipramine; Dronabinol; Female; Male; Norepinephrine; Piperidines; Prazosin; Propranolol; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Sex Characteristics; Substance Withdrawal Syndrome; Swimming; Synaptic Transmission

Abstinence symptoms in cannabis-dependent individuals are believed to contribute to the maintenance of regular marijuana use. However, there are currently no medications approved by the FDA to treat cannabis-related disorders. The only treatment currently shown consistently to alleviate cannabinoid withdrawal in both animals and humans is substitution therapy using the psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol (THC). However, new genetic and pharmacological tools are available to increase endocannabinoid levels by targeting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol, respectively. In the present study, we investigated whether increasing endogenous cannabinoids levels, through the use of FAAH (-/-) mice as well as the FAAH inhibitor URB597 or the MAGL inhibitor JZL184, would reduce the intensity of withdrawal signs precipitated by the CB(1) receptor antagonist rimonabant in THC-dependent mice. Strikingly, acute administration of either URB597 or JZL184 significantly attenuated rimonabant-precipitated withdrawal signs in THC-dependent mice. In contrast, FAAH (-/-) mice showed identical withdrawal responses as wild-type mice under a variety of conditions, suggesting that the absence of this enzyme across the development of dependence and during rimonabant challenge does not affect withdrawal responses. Of importance, subchronic administration of URB597 did not lead to cannabinoid dependence and neither URB597 nor JZL184 impaired rotarod motor coordination. These results support the concept of targeting endocannabinoid metabolizing enzymes as a promising treatment for cannabis withdrawal.

Topics: Amidohydrolases; Animals; Benzamides; Benzodioxoles; Cannabinoid Receptor Modulators; Carbamates; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Hallucinogens; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Motor Activity; Piperidines; Postural Balance; Psychomotor Performance; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome

Despite tobacco being highly addictive, it is unclear if nicotine has significant affective properties. To address this, we studied taste reactions to gustatory stimuli, palatable sucrose and unpalatable quinine, which are believed to reflect ongoing affective state. Taste reactivity was assessed during chronic nicotine administration and spontaneous withdrawal and the role of the endogenous cannabinoids was also investigated. C57BL6J mice were implanted with intraoral fistula to allow passive administration of solutions. In the first study, taste reactivity was tracked throughout chronic vehicle or nicotine (12 mg/kg/day) infusion via osmotic minipumps and spontaneous withdrawal following removal of minipumps. In the second study, the endocannabinoid CB1-receptor antagonist AM251 (1, 3 and 10mg/kg, intraperitoneal) or vehicle was acutely administered before taste reactivity measurement during chronic nicotine administration. Chronic nicotine treatment and spontaneous withdrawal did not influence taste reactions to sucrose or quinine. AM251 decreased positive reactions to sucrose and increased negative reactions to quinine. The effects of AM251 were respectively attenuated and enhanced in nicotine infused mice. These results suggest chronic nicotine exposure and withdrawal has no apparent affective sequelae, as probed by taste reactivity, and thus may not explain the difficulty tobacco-users have in achieving abstinence. In contrast, endocannabinoids elevate affective state in drug-naïve animals and changes in endogenous endocannabinoid tone may underlie compensations in affective state during chronic nicotine exposure.

Topics: Affect; Animals; Avoidance Learning; Cannabinoid Receptor Modulators; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Nicotine; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome; Taste; Tobacco Use Disorder

mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.

Topics: Analgesics, Opioid; Animals; Calcium; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Evoked Potentials; GTP-Binding Proteins; Hyperalgesia; Long-Term Potentiation; Male; Nerve Fibers, Unmyelinated; Patch-Clamp Techniques; Piperidines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Remifentanil; Signal Transduction; Substance Withdrawal Syndrome; Synapses

Converging evidence suggests that the endogenous cannabinoid (eCB) system is involved in extinction of learned behaviours. Using operant and classical conditioning procedures, the potential of the fatty acid amide (FAAH) inhibitor, URB-597, and the CB(1) antagonist/inverse agonist, SR141716, to promote and inhibit (respectively) extinction of learned responses previously motivated by either rewarding or aversive stimuli was investigated. In the operant conditioning procedure (Expt. 1), rats previously trained to lever press for sucrose reward were administered URB-597 (0.3 mg/kg) or the CB(1) antagonist/inverse agonist SR141716 (2.5 mg/kg) prior to each of three extinction trials. In the conditioned floor preference procedure (Expts 2a-d), rats trained to associate morphine with one of two distinctive floors were administered one of several doses of the CB(1) antagonist/inverse agonist, AM-251 (Expt 2a) or URB-597 (Expt 2b and 2d) prior to each extinction/test trial wherein a choice of both floors was presented and prior to forced exposure to each floor (Expt 2c). In the conditioned floor aversion procedure (Expt. 3), rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered URB-597 or SR141716 prior to each of 24 extinction/testing trials. URB-597 did not promote and SR141716 did not reduce extinction rates for sucrose reward-induced operant responding (Expt. 1) or morphine-induced conditioned floor preference (Expts. 2a-d). In contrast, URB-597 facilitated, whereas SR141716 impaired, extinction of the conditioned floor aversion (Expt. 3). These data support previous reports that the eCB system selectively facilitates extinction of aversive memories. URB-597 may prove useful in targeting extinction of aversively motivated behaviours.

Topics: Amidohydrolases; Animals; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Choice Behavior; Conditioning, Psychological; Dietary Sucrose; Extinction, Psychological; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reinforcement Schedule; Rimonabant; Species Specificity; Substance Withdrawal Syndrome

Increasing evidence suggests that marijuana abstinence leads to clinically significant withdrawal symptoms in humans. In mouse models, following chronic treatment with delta9-tetrahydrocannabinol (THC), administration of the selective cannabinoid CB1 receptor antagonist SR141716 (rimonabant) elicited varying behavioral responses, depending on mouse strain and dosing regimen. In the present study, C57BL/6 mice were injected s.c. with THC (25 mg/kg) or vehicle twice daily for 4.5 days. SR141716 (15 mg/kg) was administrated i.p. 4 h following the last THC treatment. During a 2-h observation period immediately following the SR141716 challenge, the total locomotor, ambulatory and stereotypic activities of THC-treated mice were 4.1, 3.3, and 3.8 times those of vehicle-treated mice, respectively. The number of paw tremors elicited in THC-treated mice was 111+/-11 during the 45 min immediately following SR141716, whereas only 1.1+/-0.4 was associated with vehicle-treated animals. In contrast, the number of scratching bouts was higher in vehicle-treated (182+/-20) vs THC-treated (17+/-4) mice. The present study is the first to demonstrate hyperlocomotion as an explicit sign of THC abstinence in mice. Together with paw tremors, the two unambiguous withdrawal signs may permit highly quantitative investigation of THC abstinence in C57BL/6 mice and may facilitate investigation of the mechanisms involved via both pharmacological and genetic manipulations, and ultimately potential treatments for cannabis dependence.

Topics: Analysis of Variance; Animals; Dronabinol; Dyskinesia, Drug-Induced; Forelimb; Locomotion; Male; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Psychotropic Drugs; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome; Tremor

Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting mu-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 mug/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.

Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Delayed-Action Preparations; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Morphine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Remifentanil; Self Administration; Substance Withdrawal Syndrome

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Guinea Pigs; Hot Temperature; Ileum; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Piperidines; Propane; Quaternary Ammonium Compounds; Reaction Time; Substance Withdrawal Syndrome; Time Factors

Tobacco smoking and obesity are worldwide important health problems with a growing impact in adolescent and young adults. One of the consequences of nicotine withdrawal is an increase in body weight that can act as a risk factor to relapse. Experimental therapies with a cannabinoid receptor antagonist have been recently proposed for both cigarette smoking and complicated overweight. In the present study, we aimed to investigate metabolic and hormonal effects of chronic nicotine treatment (during treatment and in abstinence) in an animal model of adolescence as well as to address the pharmacological effects of the novel selective CB1 cannabinoid receptor antagonist, SR 147778 (Surinabant). Adolescence (postnatal days 37-44) and/or post-adolescence (postnatal days 45-59) administration of Surinabant reduced body weight gain, as well as plasma glucose levels and triglycerides. The drug also reduced insulin and leptin secretion, and increased adiponectin and corticosterone levels. The effects showed sexual dimorphisms and, in general, were more pronounced in females. Chronic exposure to nicotine (0.8 mg/kg), from postnatal days 30-44 did not result in overt effects on food intake or body weight gain. However, it altered certain responses to the administration of Surinabant, both when the two drugs were given simultaneously and when Surinabant was administered during the post-adolescence period, along nicotine withdrawal. The present results indicate that the endogenous cannabinoid system is active as a metabolic modulator during adolescence and that nicotine exposure can induce long-lasting effects on metabolic regulation, altering cannabinoid modulation of energy expenditure and metabolism.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Blood Glucose; Body Weight; Cholesterol, HDL; Disease Models, Animal; Eating; Enzyme-Linked Immunosorbent Assay; Female; Hormones; Lipid Metabolism; Male; Nicotine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sex Factors; Substance Withdrawal Syndrome

There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1 receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1 receptor knockout mice. Here we have examined whether the CB1 receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10 days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.

Topics: Animals; Anxiety; Appetite; Arachidonic Acids; Autoradiography; Benzoxazines; Brain Chemistry; Cannabinoid Receptor Modulators; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Emotions; Endocannabinoids; Enkephalins; Ethanol; Ethanolamines; Glycerides; In Situ Hybridization; Male; Morpholines; Motor Activity; Naphthalenes; Neuropeptide Y; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Protein Precursors; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Stress, Psychological; Substance Withdrawal Syndrome

Polyamines are synthesized and released in high concentrations during CNS development. These agents can potentiate N-methyl-D-aspartate receptor (NMDAR) function and appear to play an important role in CNS development. Previous work has shown that polyamine release is increased during ethanol withdrawal (EWD). This likely promotes NMDAR overactivity and contributes to neurotoxicity during EWD, however, little is known regarding such effects in early neonatal brain. The present study compared the effects of EWD and polyamine exposure on toxicity in hippocampal slice cultures derived from postnatal day 2 (PND 2) or postnatal day 8 (PND 8) day-old rats. Due to changes in NMDAR subtypes and response to polyamines, we predicted that slices taken from PND 2 pups would be more sensitive to EWD and polyamine challenge.. Organotypic hippocampal slice cultures were obtained from neonatal rats either 2 or 8 days of age (PND 2 or PND 8). Five days after explantation, cultures were exposed to ETOH (50 mM- typically subthreshold for EWD induced cell death) for 10 days and then withdrawn from ETOH for 24-hour in the presence of 100 microM of the polyamine spermidine and/or 100 microM ifenprodil, an NMDAR antagonist that blocks the NMDAR that is the most sensitive to polyamine modulation. Cytotoxicity was measured after 24-hour by visualization of propidium iodide (PI) fluorescence.. There were clear age and gender-dependent differences in response to EWD and to polyamines. EWD produced significant increases in PI uptake in all subregions (CA1, CA3 and DG) of cultures derived from PND 2 pups, but not PND 8 pups. Exposure of cultures to spermidine for 24-hour also produced significant increases in cytotoxicity in all 3 regions of PND 2 cultures with no gender differences. In contrast, there were both gender and region-specific differences in response to spermidine in cultures from PND 8. While the CA1 region of both sexes displayed increased cytotoxicity following spermidine exposure, only females showed increased cytotoxicity in the CA3 region while the DG appeared relatively insensitive to spermidine. Exposure to spermidine during EWD produced enhanced toxicity in all 3 hippocampal subregions in tissue from both PND 2 and PND 8 rats and this was reduced or prevented by co-exposure to ifenprodil. Of interest, the PND 2 hippocampus was significantly more sensitive than the PND 8 hippocampus to the toxic effects of EWD and to spermidine during EWD in the DG and CA3 regions.. Hippocampal slice cultures derived from PND 2 rats were more sensitive to the toxic effects of both EWD and EWD + spermidine exposure than were those derived from PND 8 rats. These findings are similar to recent behavioral data collected from our lab showing greater sensitivity to ETOH's behavioral teratogenic effects when ETOH exposure in vivo occurred during the first postnatal week relative to the second postnatal week. Ifenprodil's ability to block the toxic effects of spermidine during EWD suggests that excess activity of NR2B subunits of the NMDAR contributed to the excitatory and cytotoxic effects of EWD plus spermidine. While no sex differences in toxicity were observed in cultures taken from pups during the first postnatal week, these data do suggest that later in neonatal life (i.e., the second postnatal week), the female hippocampus may be more sensitive to polyamine-induced neurotoxicity than males.

Topics: Aging; Animals; Animals, Newborn; Ethanol; Female; Hippocampus; Male; Organ Culture Techniques; Piperidines; Propidium; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Spermidine; Substance Withdrawal Syndrome

A growing body of evidence suggests that the endogenous cannabinoid system modulates the addictive properties of nicotine, the main component of tobacco that produces rewarding effects. In our study, complementary transgenic and pharmacological approaches were used to test the hypothesis that the endocannabinoid system modulates nicotine reward and dependence. An acute injection of nicotine elicited normal analgesic and hypothermic effects in cannabinoid receptor (CB)(1) knockout (KO) mice and mice treated with the CB(1) antagonist rimonabant. However, disruption of CB(1) receptor signaling blocked nicotine reward, as assessed in the conditioned place preference (CPP) paradigm. In contrast, genetic deletion, or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for catabolism of the endocannabinoid anandamide, enhanced the expression of nicotine CPP. Although the expression of spontaneous nicotine withdrawal (14 days, 24 mg/kg/day nicotine) was unaffected in CB(1) KO mice, acute administration of rimonabant (3 mg/kg) ameliorated somatic withdrawal signs in wild-type mice. Increasing endogenous levels of anandamide through genetic or pharmacological approaches exacerbated the physical somatic signs of spontaneous nicotine withdrawal in a milder withdrawal model (7 days, 24 mg/kg/day nicotine). Moreover, FAAH-compromised mice displayed increased conditioned place aversion in a mecamylamine-precipitated model of nicotine withdrawal. These findings indicate that endocannabinoids play a role in the rewarding properties of nicotine as well as nicotine dependence liability. Specifically, increasing endogenous cannabinoid levels magnifies, although disrupting CB(1) receptor signaling, attenuates nicotine reward and withdrawal. Taken together, these results support the hypothesis that cannabinoid receptor antagonists may offer therapeutic advantages to treat tobacco dependence.

Topics: Animals; Cannabinoid Receptor Modulators; Conditioning, Psychological; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotine; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reward; Rimonabant; Signal Transduction; Substance Withdrawal Syndrome; Tobacco Use Disorder

Preclinical and clinical research shows that the cannabinoid brain receptor type 1 (CB(1)) modulates alcohol- and nicotine-related behaviors. Throughout the nicotine-induced relapse to alcohol, the rats were pre-treated for 10 days with the CB(1) cannabinoid receptor antagonist rimonabant (0, 0.03, 0.3 and 3.0 mg/kg i.p.). In this condition, a long-lasting nicotine-induced relapse to alcohol was observed, and this effect was reversed in a dose-dependent manner with rimonabant. Surprisingly, rats that were not exposed to nicotine developed tolerance to the effects of rimonabant from the sixth day. Also, 3.0 mg/kg of rimonabant reduced the responses for sucrose. Evaluation in the Elevated Plus-Maze after nicotine treatment did not reveal anxiogenic effects. Finally, at the conclusion of rimonabant treatment, a rapid reinstatement of alcohol consumption was detected. These results suggest that rimonabant can prevent the relapse to alcohol, even when an interaction with nicotine exists-the most frequent situation in human alcohol abuse.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; Anxiety Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Synergism; Male; Maze Learning; Nicotine; Nicotinic Agonists; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Secondary Prevention; Substance Withdrawal Syndrome; Sucrose

Chronic ethanol consumption produces painful neuropathy for which there is no reliably successful therapy, largely due to a lack of understanding of the central mechanisms that underlie the development of the neuropathic pain-like state induced by chronic ethanol treatment. The aim of this study was to investigate what mechanisms contribute to the neuropathic pain-like state induced by chronic ethanol treatment in rats. Mechanical hyperalgesia was clearly observed during ethanol consumption and even after ethanol withdrawal, and lasted for 14 weeks. This hyperalgesia was significantly attenuated by repeated i.p. injection of ifenprodil, a selective NR2B subunit-containing NMDA receptor antagonist. Under these conditions, mRNA and protein levels of NR1, NR2A and NR2B subunits did not change in the spinal cord of chronic ethanol-fed rats. Interestingly, phosphorylated-Ser-1303 NR2B (p-Ser1303-NR2B) subunit was significantly increased in the spinal cord of chronic ethanol-fed rats, whereas p-Tyr1472-NR2B was not affected in the superficial spinal dorsal horn of ethanol-fed rats. These findings suggest that spinal p-Ser1303-NR2B plays a significant role in the development of the ethanol-dependent neuropathic pain-like state in rats.

Topics: Alcohol Drinking; Animals; Chronic Disease; Disease Models, Animal; Ethanol; Hyperalgesia; Immunoblotting; Immunohistochemistry; Male; Pain Threshold; Piperidines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition, and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet.. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Delta(9)-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration.. Both chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA.. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.

Topics: Animals; Brain; Cannabinoid Receptor Antagonists; Dopamine; Dose-Response Relationship, Drug; Dronabinol; Male; Mice; Mice, Inbred Strains; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Pyrazoles; Rimonabant; Serotonin; Substance Withdrawal Syndrome

Topics: Analgesics, Opioid; Humans; Hyperalgesia; Piperidines; Remifentanil; Substance Withdrawal Syndrome

Repeated marijuana use is known to lead to physical dependence in humans; however, its dependence liability has yet to be adequately assessed in laboratory animals. The goals of the present study were to: assess whether the CB(1) antagonist SR 141716 (rimonabant) precipitates withdrawal in mice that had been repeatedly exposed to marijuana smoke, and to compare these precipitated withdrawal effects to those elicited following intravenous administration of its chief psychoactive component Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716 elicited a significant increase in paw tremors in mice that were repeatedly dosed with either marijuana or Delta(9)-THC. Unexpectedly, the blood and brain concentrations of Delta(9)-THC following marijuana exposure were considerably lower than those found following Delta(9)-THC injection when comparing an equivalent magnitude of paw tremors in both conditions. Finally, Delta(9)-THC dose-dependently alleviated SR 141716-induced paw tremors in marijuana-dependent mice, but marijuana itself failed to reverse the precipitated withdrawal effect. It is likely that marijuana exposure generated insufficient Delta(9)-THC brain levels (i.e., 203+/-19 ng/g) to reverse the withdrawal signs compared with the brain levels following intravenous injection (i.e., 1862+/-82 ng/g). These findings taken together indicate that mice exposed repeatedly to marijuana smoke exhibit similar precipitated withdrawal effects as Delta(9)-THC-injected mice.

Topics: Animals; Cannabis; Male; Mice; Mice, Inbred ICR; Piperidines; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome; Substance-Related Disorders

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.

Topics: Animals; Calcitonin Gene-Related Peptide; Cannabinoid Receptor Modulators; Cannabinoids; Capsaicin; Drug Administration Schedule; Endocannabinoids; Ganglia, Spinal; Hot Temperature; Immunologic Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Opioid-Related Disorders; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome

Stress impairs hippocampal long-term potentiation (LTP), but it is unknown whether the stress evoked by opiate withdrawal has the same effect. Here the authors report that opiate withdrawal for 4 days does not influence basal synaptic transmission, but results in a greatly increased LTP in hippocampal CA1 area in anesthetized rats. Elevated-platform stress enabled a large LTP in rats withdrawn for only 18 h, but the glucocorticoid receptor antagonist RU38486 (twice per day for 3 days) prevented the large LTP on 4 days withdrawal. Moreover, 4 days withdrawal enhanced the NMDAR-mediated EPSCs, in which the NR2A-containing NMDAR-mediated EPSC was increased but the NR2B-containing NMDAR-mediated EPSC was decreased. These results suggest that adaptive changes of the NMDAR and glucocorticoid receptor functions during 4 days of opiate withdrawal may enable stress to facilitate hippocampal LTP, potentially contributing to the opiate withdrawal experience-dependent modifications of hippocampal functions.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Dose-Response Relationship, Radiation; Drug Administration Schedule; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Hormone Antagonists; In Vitro Techniques; Long-Term Potentiation; Male; Mifepristone; Morpholines; Patch-Clamp Techniques; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Stress, Psychological; Substance Withdrawal Syndrome; Time Factors

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drug-seeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drug-seeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.

Topics: Acoustic Stimulation; Animals; Cues; Dopamine; Environment; Extinction, Psychological; Light; Male; Motivation; Motor Activity; Nicotine; Nicotinic Agonists; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Self Administration; Substance Withdrawal Syndrome; Synaptic Transmission; Tobacco Use Disorder

Numerous recent studies have reported major functional interactions between cannabinoid and opioid systems. These interactions can be studied in the myenteric plexus-longitudinal muscle isolated preparations. We had previously shown that in the guinea-pig ileum (GPI), the opioid acute withdrawal response is under the inhibitory control of several systems; mu-opioid agonist exposure indirectly activates the kappa-opioid system; conversely, exposure to a kappa-opioid agonist indirectly activates the mu-system; the indirectly activated opioid system inhibits the withdrawal response. The adenosine A1 system is also indirectly activated by opioids and it inhibits the withdrawal response. We had also shown that indirect activation is prevented or antagonized by cholecystokinin (CCK-8). In GPI preparations briefly exposed to the mu-agonist, dermorphine (DERM) and then challenged with naloxone (NL), the cannabinoid CB1 antagonist, SR141716 (SR), increased the withdrawal responses to NL, but only did so in presence of a kappa-opioid and an adenosine A(1) antagonist. Under similar experimental conditions, SR also enhances the kappa-opioid withdrawal response. In opioid agonist/CCK-8/NL tests, SR antagonized the inhibition of the tissue response to CCK-8 induced by the mu- or kappa-opioid agonist and increased the kappa-withdrawal response, but not the mu-withdrawal response. However, the dose-response curve against dermorphine inhibition of the response to CCK-8 was bell-shaped and the highest SR concentration also significantly decreased the mu-withdrawal response. In preparations exposed to dermorphine or to the kappa-agonist, U-50,488H, the cannabinoid agonist WIN 55,212-2 increased the opioid-induced inhibition of the tissue response to CCK-8 and decreased the NL-induced responses. These results show that opioid exposure may also activate the cannabinoid CB1 system, which leads to an inhibition of the opioid acute withdrawal response. This phenomenon and the antagonistic effect of SR on the opioid-induced inhibition of the response to CCK-8 suggest that reciprocal interaction between opioid and cannabinoid systems are operating in the enteric nervous system.

Topics: Acute Disease; Adenosine A1 Receptor Antagonists; Analgesics, Opioid; Animals; Benzoxazines; Cholecystokinin; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morpholines; Muscle Contraction; Muscle, Smooth; Naloxone; Naphthalenes; Narcotic Antagonists; Neurons; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Opioid, kappa; Receptors, Opioid, mu; Rimonabant; Substance Withdrawal Syndrome; Theophylline

Topics: Adult; Aged; Conscious Sedation; Drug Tolerance; Female; Humans; Hypnotics and Sedatives; Intensive Care Units; Male; Piperidines; Remifentanil; Substance Withdrawal Syndrome; Time Factors

JDTic, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide, is a potent and selective kappa-opioid antagonist with a very long duration of action [Carroll, F.I., Thomas, J.B., Dykstra, L.A., Granger, A.L., Allen, R.M., Howard, J.L., Pollard, G.T., Aceto, M.D., Harris, L.S., 2004. Pharmacological properties of JDTic: A novel k-opioid receptor antagonist. Eur. J. Pharmacol. 501, 111-119.]. When given 24 h prior to a continuous 4-day infusion of morphine sulfate in rats, JDTic did not prevent the stereotypy that developed during the infusion of morphine. It had no effect on the dramatic loss of body weight associated with the abrupt withdrawal of morphine. However, it decreased the number of important withdrawal signs designated wet-dog shakes and facial rubs. These data suggest that JDTic may find some application in the treatment of opiate abuse.

Topics: Animals; Behavior, Animal; Body Weight; Infusion Pumps; Injections, Intraperitoneal; Male; Models, Animal; Morphine; Morphine Dependence; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Substance Withdrawal Syndrome; Tetrahydroisoquinolines; Time Factors

Cannabinoid withdrawal has been indicated in both human and animal subjects. One of pathways proposed to facilitate cannabinoid action is the arachidonic acid cascade. Previously, we have shown that prostaglandin attenuated the expression of withdrawal signs in tetrahydrocannabinol-dependent mice. It follows that the cascade might participate in the expression of cannabinoid withdrawal. We utilized a quasi abstinence approach (the induction of a state of cannabinoid withdrawal without giving any cannabinoid substances in a naïve animal) to describe the relationship between the change in prostaglandin level, an end product of the arachidonic acid cascade, and the expression of cannabinoid withdrawal. Administration of 10 mg/kg diclofenac, a prostaglandin synthesis inhibitor, i.p. 30 min before SR 141716A induced cannabinoid withdrawal signs in naïve mice, which were comparable to the true abstinence in cannabinoid-tolerant mice. In turn, 10 mg/kg Delta(8)-THC i.p., given 15 min prior to SR 141716A, blocked the expression of these signs. These results suggested that the decrease in prostaglandin level is a prerequisite for the expression of cannabinoid withdrawal.

Topics: Animals; Behavior, Animal; Cannabinoids; Cyclooxygenase Inhibitors; Diclofenac; Dronabinol; Male; Mice; Piperidines; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome; Weight Loss

Chronic treatment with cannabinoid agonists leads to tolerance. One possible mechanism for this is receptor internalization, but tolerance has also been reported with compounds that only cause internalization to a low degree. Furthermore, cannabinoid antagonist administration precipitates a characteristic withdrawal syndrome in tolerant subjects, accompanied by neuronal activation and enhanced release of corticotropin-releasing hormone (CRH) in the central amygdala. The underlying molecular mechanisms are unknown. We examined the role of cannabinoid tolerance and withdrawal for the expression of the cannabinoid 1 (CB1) receptor and of CRH in rats. Tolerance was first established functionally. An acute dose (100 microg/kg) of the CB1 agonist HU-210 suppressed locomotor activity, and had an anxiogenic-like effect on the elevated plus-maze. Both effects were absent following daily treatment with the same agonist or a lower (40 microg/kg) dose for 14 days. Next, withdrawal was reliably precipitated by a single dose (3 mg/kg) of the CB1 antagonist SR141716A in rats treated subchronically with 14-day HU-210. Using in situ hybridization, a robust suppression of CB1 mRNA expression was found in the caudate-putamen, indicating a downregulation of CB1 expression levels as one mechanism for tolerance to the locomotor suppressant effects of HU-210. The CRH transcript was upregulated in the central amygdala in precipitated withdrawal compared to nonwithdrawn tolerant subjects, suggesting that increased gene expression contributes to the previously reported CRH release in withdrawal. Most importantly, this increase occurred from a suppressed level in tolerant subjects, and behavioral signs of withdrawal, presumably mediated by CRH, were seen at the CRH expression that had only returned to normal nontolerant levels. This suggests the possibility of an allostatic shift, as previously proposed on theoretical grounds. The expression of CRH-R1, CRH-R2alpha, NPY, and its Y1 receptor mRNA was analyzed in search of neural substrates for the allostatic shift observed, but did not seem to contribute to the dysregulated state.

Topics: Amygdala; Analysis of Variance; Animals; Behavior, Animal; Cannabinoids; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Dronabinol; Drug Administration Schedule; Drug Tolerance; Excitatory Amino Acid Antagonists; Gene Expression Regulation; In Situ Hybridization; Locomotion; Male; Maze Learning; Neostriatum; Neuropeptide Y; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Rimonabant; RNA, Messenger; Substance Withdrawal Syndrome; Time Factors

Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB(1) receptor) in Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Delta(9)-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion-these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Delta(9)-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Delta(9)-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Delta(9)-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Delta(9)-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Delta(9)-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Delta(9)-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB(1) receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compare

Topics: Animals; Arachidonic Acids; Behavior, Animal; Brain; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Corticosterone; Dronabinol; Drug Administration Schedule; Drug Tolerance; Endocannabinoids; Glycerides; Male; Paraventricular Hypothalamic Nucleus; Piperidines; Polyunsaturated Alkamides; Prolactin; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Corticotropin-Releasing Hormone; Rimonabant; RNA, Messenger; Substance Withdrawal Syndrome

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg(-1), s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg(-1), intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 micrograms) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg(-1), i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal.

Topics: Animals; Benzoxazines; Brain; Cannabinoids; Dose-Response Relationship, Drug; Male; Mice; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance Withdrawal Syndrome

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.

Topics: Amidines; Amphetamines; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endocrine System Diseases; Estradiol; Estrogens; Female; Fluorobenzenes; Naloxone; Ovariectomy; Piperidines; Rats; Reaction Time; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Serotonin Receptor Agonists; Skin Temperature; Substance Withdrawal Syndrome; Telemetry; Time Factors

The present study aimed to clarify the role of the arachidonic acid cascade in mediating the expression of withdrawal signs in cannabinoid-dependent mice. Mice were injected with Delta(8)-tetrahydrocannabinol (THC) at 20 mg/kg (i.p.) every 12 h, 11 times. When SR141716A, a specific cannabinoid CB1 receptor antagonist, at 10 mg/kg (i.p.) was given 4 h after the last THC injection, withdrawal signs such as forepaw licking, facial preening, grooming, forepaw tremor, head shakes and weight loss were clearly observed. PGE(2) at 0.1, 1.0 and 3.2 microg (per animal; i.c.v.) given prior to SR141716A (10 mg/kg, i.p.) dose-dependently decreased the number of forepaw licking, facial preening, grooming and forepaw tremor episodes. Instead of SR141716A, a cyclooxygenase inhibitor diclofenac at 10 mg/kg (i.p.) also precipitated these withdrawal signs. The results suggest that the expression of THC withdrawal is due to a decrease in prostaglandin levels through inactivation of the arachidonic acid cascade in the brain.

Topics: Animals; Cannabinoids; Dinoprostone; Dose-Response Relationship, Drug; Dronabinol; Male; Mice; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

We report two cases of discontinuation syndrome on cessation of donepezil treatment. The clinical presentations are described and diagnostic criteria is appendixed.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia; Donepezil; Female; Humans; Indans; Middle Aged; Nootropic Agents; Piperidines; Substance Withdrawal Syndrome

Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction.

Topics: Acetylcholine; Animals; Cholinesterase Inhibitors; Cocaine; Cocaine-Related Disorders; Conditioning, Psychological; Donepezil; Indans; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Nucleus Accumbens; Pain; Piperidines; Substance Withdrawal Syndrome

The effects of chronic exposure to cannabinoids on short-term memory in rats were assessed during repeated daily injections of an initially debilitating dose (3.75 mg/kg) of the potent CB1 cannabinoid receptor ligand, WIN 55,212-2. Delayed nonmatch to sample (DNMS) performance was assessed over a 35-day exposure period in which performance was initially disrupted during the first 21 days of exposure but recovered by day 30 and was stable at pre-drug levels for 5 days thereafter. Withdrawal was precipitated by injections of the CB1 receptor antagonist SR141716A and transiently reduced performance for 2 days but was restabilized to pre-drug levels within 3-4 days. Concomitant recording from identified CA1 and CA3 hippocampal neurons demonstrated a marked correspondence in the time course of suppression of peak firing in the sample and delay phases of the task to the drug-induced performance deficits over the same days of exposure. Hippocampal encoding of task-relevant events and performance levels "tracked" each other on a daily basis throughout the chronic cannabinoid treatment and withdrawal regimen. However, hippocampal neuronal activity in the nonmatch phase of the task was unaffected by the chronic cannabinoid treatment or withdrawal, suggesting that only a select population of hippocampal neurons and synapses are involved in cannabinoid-sensitive short-term memory processes.

Topics: Action Potentials; Adaptation, Physiological; Animals; Benzoxazines; Cannabinoids; Drug Administration Schedule; Drug Tolerance; Hippocampus; Male; Marijuana Abuse; Memory Disorders; Morpholines; Naphthalenes; Neurons; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Reaction Time; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome; Synaptic Transmission

This study examined whether the cannabinoid antagonist, SR 141716A, could be established as a discriminative stimulus in rhesus monkeys treated with delta -sup-9-tetrahydrocannabinol (delta -sup-9-THC). Stimulus control was established with SR 141716A (1.0 mg/kg) in 3 delta -sup-9-THC-treated monkeys (1.12 mg/kg/day) in 113-124 sessions. The SR 141716A discriminative stimulus was dose related, attenuated by an acute injection of delta -sup-9-THC, and not mimicked by cocaine or ketamine. SR 141716A-appropriate responding occasioned by temporary discontinuation of delta -sup-9-THC treatment was attenuated by delta -sup-9-THC and not ketamine. The SR 141716A discriminative stimulus in delta -sup-9-THC-treated monkeys appears to be mediated by cannabinoid receptors and could be related to delta -sup-9-THC withdrawal.

Topics: Anesthetics; Animals; Behavior, Animal; Cannabinoids; Cocaine; Discrimination Learning; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Female; Ketamine; Macaca mulatta; Male; Photic Stimulation; Piperidines; Psychotropic Drugs; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome

This study examined the intracerebroventricular (i.c.v.) effects of three selective tachykinin receptor antagonists on the cardiovascular and behavioural responses induced by naloxone-precipitated morphine withdrawal in rats. I.c.v. injection of naloxone (10 microg) to morphine pre-treated rats (i.c.v. for 5 days) induced an immediate increase in blood pressure ( approximately 10 mmHg) and behavioural activity (sniffing > rearing > face washing approximately grooming approximately wet dog shake) without causing significant heart rate changes. The prior i.c.v. injection of the NK(1) receptor antagonist (6.5 nmol LY306740) reduced face washing and grooming during morphine withdrawal. NK(2) and NK(3) receptor antagonists (6.5 nmol SR48968 and R820) did not affect behavioural effects, yet the co-injection of the three tachykinin antagonists reduced all behavioural activity. The pressor response was not affected by the selective inhibition of NK(1) and NK(3) receptors while both blood pressure and heart rate were markedly enhanced by SR48968 during morphine withdrawal. The potentiating effect of SR48968 was prevented following simultaneous blockade of the three tachykinin receptors. In addition to confirming the involvement of central tachykinins in behavioural manifestations to morphine withdrawal, data suggest a modulatory function for tachykinins, especially the NK(2) receptor, in brain autonomic control of blood pressure and heart rate in supraspinal noloxone-precipitated withdrawal.

Topics: Acetamides; Animals; Behavior, Animal; Benzamides; Blood Pressure; Heart Rate; Indoles; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Oligopeptides; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Substance Withdrawal Syndrome; Tachykinins

The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on -methyl-D-aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for potentiation of NMDAR function during ethanol withdrawal, we evaluated the effects of acamprosate, MK-801, and ifenprodil in a cell culture model of ethanol withdrawal-induced neurotoxicity.. Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in vitro for 23 days before experimental use. The ethanol withdrawal model consisted of exposing cultures to ethanol (70-100 mM) for 4 days before being "withdrawn" into Calcium-Locke's buffer for 1 hr and then into minimal medium for 23 hr. Uptake of (45)CaCl(2) and propidium iodide by damaged cells was assessed 1 hr and 24 hr after the start of ethanol withdrawal, respectively. Additional studies examined effects of exposure to NMDA (50 microM) or spermidine (100 microM) on withdrawal-induced hippocampal damage. Last, these studies examined the ability of the sodium salt of acamprosate (Na-acamprosate, 200 microM), ifenprodil (50 microM), or MK-801 (30 microM) to inhibit neurotoxicity and (45)Ca(2+) entry produced by these insults.. Ethanol withdrawal was associated with significantly greater toxicity and (45)Ca(2+) entry, relative to controls. Exposure to spermidine and NMDA during ethanol withdrawal further increased neurotoxicity and (45)Ca(2+) entry. Acamprosate, ifenprodil, and MK-801 almost completely prevented ethanol withdrawal-induced toxicity and (45)Ca(2+) entry. Acamprosate also reduced spermidine-induced neurotoxicity during ethanol withdrawal but was ineffective against NMDA-induced toxicity or (45)Ca(2+) entry at this time.. The results support the contention that acamprosate, like ifenprodil, interacts with polyamines and that these compounds may be effective in reducing consequences of ethanol withdrawal. NMDAR activation is also strongly implicated in ethanol withdrawal neurotoxicity, but whether acamprosate causes any of these effects in this preparation directly via the NMDAR remains uncertain.

Topics: Acamprosate; Animals; Animals, Newborn; Calcium Signaling; Dizocilpine Maleate; Ethanol; Female; Hippocampus; Male; Organ Culture Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Taurine

Recent studies suggest that the protein tyrosine kinase Fyn constitutes a determinant of fear and anxiety as well as alcohol sensitivity in mice. We investigated these functions and their relatedness in mice with transgenic over-expression of native or mutated, constitutively active Fyn. Fear- and anxiety-related behaviour of these animals were normal under varying levels of stress, but under withdrawal from alcohol both types of transgenic mice failed to show any increase of anxiety-like behaviour or reduction of exploratory activity as seen in their wild-type littermates. This apparent lack of alcohol withdrawal-induced behavioural effects was associated with increased Fyn activity and tyrosine phosphorylation of several proteins including the NMDA receptor subunit NR2B in the different mutant lines. NR2B phosphorylation itself remained unaffected by the chronic alcohol ingestion and subsequent withdrawal, but challenge with an NR2B antagonist, ifenprodil, restored a normal behavioural response in alcohol-withdrawn fyn mutants. Moreover, both types of transgenic mice showed a reduction of voluntary alcohol consumption compared to their wild-type littermates. Together, these results suggest that Fyn can modulate alcohol consumption and prevent behavioural changes during alcohol withdrawal, possibly via phosphorylation of NR2B.

Topics: Aggression; Alcohol-Induced Disorders, Nervous System; Animals; Anxiety; Behavior, Animal; Brain; Drug Resistance; Ethanol; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fear; Female; Genotype; Male; Mice; Mice, Transgenic; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fyn; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cannabinoids; Crosses, Genetic; Dronabinol; Drug Tolerance; Hypothermia; Marijuana Abuse; Mice; Mice, Inbred Strains; Mice, Knockout; Motivation; Motor Activity; Piperidines; Psychotropic Drugs; Pyrazoles; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reward; Rimonabant; Spatial Behavior; Substance Withdrawal Syndrome

The present study investigated the effect of the cannabinoid CB(1) receptor antagonist, SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), on alcohol deprivation effect (i.e. the temporary increase in alcohol intake after a period of alcohol withdrawal) in Sardinian alcohol-preferring (sP) rats. As expected, alcohol-deprived rats virtually doubled voluntary alcohol intake during the first hour of re-access. Acute administration of SR 141716 (0, 0.3, 1 and 3 mg/kg, i.p.) completely abolished the alcohol deprivation effect. These results suggest that the cannabinoid CB(1) receptor is part of the neural substrate mediating the alcohol deprivation effect and that SR 141716 may possess anti-relapse properties.

Topics: Alcohol Drinking; Analysis of Variance; Animals; Cannabinoids; Male; Piperidines; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

The newly reported benzoflavone moiety from the plant Passiflora incarnata Linneaus has been evaluated in light of traditional reports on the use of P. incarnata in breaking down cannabis addiction. In the modern or allopathic system of therapeutics, there has been no suitable remedy to combat the severe withdrawal effects of various cannabis products, including marihuana, marijuana, bhang, hashish, ganja, etc., the world-wide consumption of which has attained alarming proportions especially among the younger generation. Mice were given a 10-mg-kg(-1) twice-daily dose of delta9-tetrahydrocannabinol (delta9-THC) by mouth for six days to make them dependent upon cannabinoids. Concurrently, other groups of mice were administered delta9-THC along with a 10- or 20-mg-kg(-1) twice-daily dose of the benzoflavone moiety from P. incarnata orally for 6 days. Upon measuring locomotor activity during the treatment regimen, it was noticed that the mice receiving the P. incarnata extract and delta9-THC together developed significantly less tolerance and dependence, relative to the mice receiving delta9-THC alone. Upon administration of SR-141716A, a selective cannabinoid-receptor antagonist (10 mg kg(-1), p.o.) to all the groups of mice on the 7th day, an artificial withdrawal was produced due to an abrupt decline of delta9-THC levels in mouse brain. However, the typical withdrawal effects like paw tremors and head shakes were significantly less in the mice given delta9-THC+P. incarnata benzoflavone moiety for 6 days. Upon administration of 20 mg kg(-1) of the P. incarnata benzoflavone moiety to mice showing severe symptoms of withdrawal due to administration of SR-141716A, there was a marked attenuation of withdrawal effects, thereby suggesting the usefulness of the benzoflavone moiety in delta9-THC withdrawal. Thus, the benzoflavone moiety of P. incarnata, when administered concurrently with delta9-THC, prevented the development of tolerance and dependence of cannabinoids in mice. Even an acute administration of the benzoflavone moiety (20 mg kg(-1), p.o.) significantly blocked the expression of withdrawal effects in delta9-THC-dependent mice.

Topics: Administration, Oral; Animals; Benzoflavones; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Hallucinogens; Methanol; Mice; Motor Activity; Passiflora; Piperidines; Plant Extracts; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Solvents; Substance Withdrawal Syndrome

Physical dependence on the synthetic cannabinoid-receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN 55212-2) was demonstrated in rats by the use of a chronic continuous infusion. Spontaneous withdrawal, of moderate intensity, was shown for the first time with this class of drugs of abuse. Behavioral withdrawal signs were also elicited after challenge with (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A), a specific CB(1) cannabinoid-receptor antagonist. In both instances, the high-dose regimen (4, 8, 16 and 16 mg/kg/day, i.p. on days 1-4, respectively) was sufficient to evoke a typical withdrawal syndrome quantified by the signs wet-dog shakes and facial rubs. These results are discussed relative to those obtained with Delta(9)-tetrahydrocannabinol and anandamide. With Delta(9)-tetrahydrocannabinol, precipitated but not spontaneous or abrupt withdrawal was observed, and this was ascribed to pharmacokinetic properties. Anandamide, which showed little, if any, physical dependence potential, behaved atypically. Possible implications regarding pharmacotherapeutic and human abuse issues are discussed.

Topics: Animals; Behavior, Animal; Benzoxazines; Body Weight; Cannabinoids; Dose-Response Relationship, Drug; Male; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Substance Withdrawal Syndrome; Time Factors

Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB(1) antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB(1) antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB(1) antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB(1) receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB(1) antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction.

Topics: Animals; Brain Chemistry; Cannabinoids; Conditioning, Operant; Dynorphins; Male; Mice; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Piperidines; Pyrazoles; Radioimmunoassay; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid, kappa; Rimonabant; Substance Withdrawal Syndrome; Synapses

The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB(1) cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716A-precipitated Delta(9)-THC withdrawal was ameliorated in mu-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB(1) cannabinoid receptors. An acute injection of morphine in Delta(9)-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.03--0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04--0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in mu-opioid knockout mice and was significantly decreased in CB(1) cannabinoid receptor knockout mice. Acute treatment of Delta(9)-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD(50) (95% CL) = 0.5 (0.3--1.0), and head shakes AD(50) (95% CL) = 0.6 (0.57--0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Delta(9)-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the mu-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.

Topics: Animals; Behavior, Animal; Cannabinoids; Diarrhea; Dronabinol; Drug Implants; Hallucinogens; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Knockout; Morphine; Morphine Dependence; Narcotics; Opioid Peptides; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid, mu; Rimonabant; Substance Withdrawal Syndrome

We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. Capsaicin cream applied to both the bilateral hind instep and sole once a day for a continuous period of 2 weeks or 4 weeks alleviated thermal hyperalgesia in a dose-dependent manner. A remarkable effect was observed 2 weeks after the start of the application and this effect proved to be reversible. On the other hand, in sham-operated animals when capsaicin cream was applied once daily from day 7 after the sham operation, from 1 day through 3 weeks following capsaicin application, withdrawal latency of the sham-operated paws of the capsaicin-treated group was significantly increased as compared to that of the vehicle cream-treated group. The effects of antagonists of glutamate receptor and tachykinin receptors were investigated 7 days post surgery. Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Animals; Benzamides; Capsaicin; Carrageenan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Indoles; Isoindoles; Male; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Piperidines; Postoperative Period; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Substance Withdrawal Syndrome; Time Factors

Rats were trained to lever press according to variable interval 10 s schedules during daily experimental sessions composed of six 3 min food reinforcement periods and were treated twice daily for 6 days with either vehicle or escalating regimens of Delta(9)-tetrahydrocannabinol. On days 7 and 8, the rats were challenged with vehicle and cumulative doses of SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4, -dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), a cannabinoid CB(1) receptor antagonist, up to 3 and 9 mg/kg, respectively. Response rates increased during Delta(9)-tetrahydrocannabinol withdrawal and towards those of the vehicle treatment group suggesting a waning of the direct effects of Delta(9)-tetrahydrocannabinol. SR141716A reduced response rates but only in rats pre-treated with Delta(9)-tetrahydrocannabinol. These data suggest that dependence upon Delta(9)-tetrahydrocannabinol was induced and SR141716A precipitated withdrawal.

Topics: Animals; Dose-Response Relationship, Drug; Dronabinol; Male; Piperidines; Psychotropic Drugs; Pyrazoles; Rats; Rats, Long-Evans; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome; Substance-Related Disorders

Region-specific up-regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium-calmodulin-stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up-regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp-8Br-cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up-regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenylyl Cyclases; Animals; Behavior, Animal; Cerebellum; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dronabinol; Enzyme Activation; Hallucinogens; Injections; Injections, Intraventricular; Male; Mice; Piperidines; Pyrazoles; Receptors, Drug; Rimonabant; Stereotaxic Techniques; Substance Withdrawal Syndrome; Up-Regulation

There is evidence that cannabinoids cause tolerance and physical dependence in humans and animals.. The aim of this work was to study whether the endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), induced behavioral tolerance and physical dependence in rats.. Rats were injected with anandamide (20 mg/kg i.p.) daily for 2 weeks. To assess tolerance, on days 1, 8 and 15 of treatment rats were observed and behavior was tested. Two common methods were employed to assess physical dependence: interruption of anandamide dosing and vehicle substitution or administration of the cannabinoid CB1 receptor antagonist SR141716A (3 mg/kg i.p.).. Full or partial tolerance developed to the classical behavioral effects elicited by the cannabinoids: hypothermia, catalepsy, hypomotility, decrease in stereotypic activity (rearing and grooming) and hindlimb splaying. No tolerance to anandamide was observed for reduced defecation. An abstinence syndrome appeared after abrupt cessation of cannabinoid intake and after withdrawal precipitated by SR141716A; the withdrawal signs were scratching, licking and biting, eating of feces, ptosis, arched back, wet dog shakes, head shakes, myoclonic spasms, writhing, forepaw fluttering, teeth chattering and piloerection.. These findings indicate that the endogenous cannabinoid ligand, administered exogenously, induces both tolerance and physical dependence in rats.

Topics: Animals; Arachidonic Acids; Calcium Channel Blockers; Drug Tolerance; Endocannabinoids; Male; Piperidines; Polyunsaturated Alkamides; Psychomotor Performance; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

The role of the cannabinoid system in morphine withdrawal was examined through long-term CB1 receptor antagonist administration in morphine pellet implanted rats. SR141716A chronic treatment (5mg/kg i.p. twice a day for four days) did not influence the development of tolerance to the morphine analgesic effect but significantly reduced the intensity of naloxone-induced opiate withdrawal in tolerant rats: Specifically there was a significant reduction in the number of digging, teeth chattering and penile licking and the incidence of diarrhoea while other signs such as writhing, head dog shakes and rearing were unaffected. These results suggest that the pharmacological treatment with SR141716A could be of some interest in ameliorating opiate withdrawal syndrome.

Topics: Analysis of Variance; Animals; Cannabinoids; Dogs; Drug Interactions; Drug Tolerance; Male; Morphine; Morphine Dependence; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acoustic Stimulation; Animals; Body Temperature; Columbidae; Corticosterone; Depression; Discrimination Learning; Drug Interactions; Fluoxetine; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Lip; Male; Microdialysis; Neurons; Nicotine; Piperidines; Posture; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Reflex, Startle; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Smoking Cessation; Substance Withdrawal Syndrome; Sulfur Radioisotopes

The present study was designed to further investigate the direct involvement of the NR2B-containing NMDA receptor in ethanol dependence. Using the liquid diet method, mice were chronically treated with skimmed milk containing 5% ethanol for 5 days. After the discontinuation of ethanol, mice revealed tremor, handling-elicited convulsion and death. Treatment with a selective NR2B-containing NMDA receptor antagonist, ifenprodil, significantly suppressed the expression of ethanol withdrawal signs. The protein level of NR2B subunits in the limbic forebrain, but not the cerebral cortex, during chronic ethanol treatment was markedly increased with respect to the levels in control mice. The significant up-regulation of NR2B subunits lasted for at least 9 h after the discontinuation of ethanol and returned to the basal level by 48 h after the withdrawal. These findings suggest that the up-regulation of NR2B subunits during chronic ethanol exposure may be implicated in the initial development of physical dependence on ethanol.

Topics: Animals; Ethanol; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred C57BL; Piperidines; Prosencephalon; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

We wished to investigate further the hypothesis of an endogenous cannabinoid 'aversive counter-rewarding system, as the rewarding properties of cannabinoids using standard procedures remain ambiguous.. The purpose of this study was to confirm the behavioural effects of a highly potent synthetic cannabinoid agonist (HU210) and the selective cannabinoid antagonist SR 141716A using conditioned place preference (CPP).. HU210 (20, 60 and 100 microg kg(-1), SR141716A (0.25, 0.5, 2 and 3 mg kg(-1)), cocaine (15 mg kg(-1) and delta9-THC (1.5 mg kg(-1)) were given to male Lister hooded rats using an unbiased CPP design.. SR141716A and cocaine produced place preference at all doses tested, whereas HU210 and delta9-THC produced aversion as expressed by time spent in the drug-paired compartment of the CPP apparatus.. The aversive effects of cannabinoid agonists and the rewarding effect of the cannabinoid antagonist are suggestive of a cannabinergic tone in the rat brain. Further research is needed to determine the precise relationship of that tone with the reward pathways of the brain.

Topics: Animals; Avoidance Learning; Cannabinoids; Conditioning, Psychological; Dronabinol; Male; Piperidines; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, Drug; Reward; Rimonabant; Substance Withdrawal Syndrome

The tolerance and dependence after chronic medication with morphine are thought to be representative models for studying the plasticity, including the remodeling of neuronal networks. To test the hypothesis that changes in neuronal plasticity observed in opioid tolerance or dependence are derived from increased activity of the anti-opioid nociceptin system, the effects of chronic treatments with morphine were examined using nociceptin receptor knock-out (NOR(-/-)) mice and a novel nonpeptidic NOR antagonist, J-113397, which shows a specific and potent NOR antagonist activity in in vitro [(35)S]GTPgammaS binding assay and in vivo peripheral nociception test. The NOR(-/-) mice showed marked resistance to morphine analgesic tolerance without affecting morphine analgesic potency in tail-pinch and tail-flick tests. The NOR(-/-) mice also showed marked attenuation of morphine-induced physical dependence, manifested as naloxone-precipitated withdrawal symptoms after repeated morphine treatments. Similar marked attenuation of morphine tolerance was also observed by single subcutaneous (10 mg/kg) or intrathecal (1 nmol) injection of J-113397, which had been given 60 min before the test in morphine-treated ddY mice. However, the intracerebroventricular injection (up to 3 nmol) did not affect the tolerance. On the other hand, morphine dependence was markedly attenuated by J-113397 that had been subcutaneously given 60 min before naloxone challenge. There was also observed a parallel enhancement of NOR gene expression only in the spinal cord during chronic morphine treatments. Together, these findings suggest that the spinal NOR system develops anti-opioid plasticity observed on morphine tolerance and dependence.

Topics: Animals; Benzimidazoles; Binding, Competitive; Brain; Cell Membrane; Disease Models, Animal; Drug Administration Schedule; Drug Antagonism; Drug Tolerance; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Neuronal Plasticity; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain Measurement; Piperidines; Receptors, Opioid; Spinal Cord; Substance Withdrawal Syndrome

Evidence is starting to accumulate that NK1 receptor antagonists might have anxiolytic effects in animal tests and in patients.. To examine the effects of NKP608, a substance P antagonist acting at NK1 receptors, in various conditions of the social interaction test of anxiety and to determine its effects after 3 and 6 weeks of treatment.. Rats were tested after vehicle, 0.01 or 0.1 mg/kg PO in three conditions of the social interaction test that varied in the level of anxiety generated. Thus pairs of rats were tested in an arena with which they were unfamiliar that was lit by high (HU) or low (LU) light and in the condition that generated the lowest level of anxiety, i.e. an arena with which they were familiar, lit by low light (LF). They were also tested after 3 and 6 weeks of treatment with 0.03 mg/kg and after 24 h withdrawal from these chronic treatments.. NKP608 had significant anxiolytic effects at 0.01, 0.03 and 0.1 mg/kg PO in the HU and LU test conditions, but was without effect in the LF condition, except for an increased incidence of bite attacks at 0.1 mg/kg. The anxiolytic effect of 0.03 mg/kg remained after 3 weeks of chronic treatment and there was no anxiogenic effect after 24 h of drug withdrawal. Following 6 weeks of chronic treatment (0.03 mg/kg per day), tolerance had developed, but no anxiogenic withdrawal effect was seen 24 h after the last dose.. These results provide further evidence that substance P may play a role in mediating states of anxiety and suggest that the selective NK1 receptor antagonist NKP608 may prove a useful anxiolytic compound.

Topics: Aggression; Animals; Anti-Anxiety Agents; Interpersonal Relations; Male; Motor Activity; Neurokinin-1 Receptor Antagonists; Piperidines; Quinolines; Rats; Substance Withdrawal Syndrome

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Delta9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.

Topics: Acute Disease; Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Body Temperature; Body Weight; Brain; Chronic Disease; Dronabinol; Drug Tolerance; Enkephalins; Hyperalgesia; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Protein Precursors; Psychotropic Drugs; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

Naltrexone hydrochloride is a synthetic opioid receptor antagonist recently used in efforts to provide rapid opioid detoxification. Other clinical uses include alleviating itch due to cholestasis or uraemia. We report a case where unrecognised naltrexone therapy for itch affected anaesthesia, resulting in high opioid requirements. We also discuss other analgesic options utilized.

Topics: Aged; Analgesics, Opioid; Arteriovenous Fistula; Debridement; Female; Foot Ulcer; Humans; Intraoperative Complications; Naltrexone; Narcotic Antagonists; Piperidines; Remifentanil; Substance Withdrawal Syndrome

Rats were administered daily for 8 days with increasing doses (2-12 mg/kg/day) of delta9-tetrahydrocannabinol (delta9-THC) and than challenged with different doses of SR141716A, an antagonist of cannabinoid receptors. SR141716A dose dependently reduced dialysate dopamine (DA) in the nucleus accumbens shell and precipitated a physical withdrawal syndrome. No such effects were obtained after administration of SR141716A to saline controls.

Topics: Animals; Behavior, Animal; Cannabinoids; Dopamine; Dronabinol; Hallucinogens; Male; Microdialysis; Nucleus Accumbens; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome; Substance-Related Disorders

The aim of the present study was to examine the influence of ifenprodil (a non-competitive NMDA receptor antagonist which also blocks 5-HT3 receptors and alpha1-adrenoceptors) on the effects of ethanol in the mouse in vivo and to elucidate the role of various receptors in these actions. The ethanol (4 g/kg i.p.)-induced sleeping time was shortened by ifenprodil 1 mg/kg but was not affected by ifenprodil 0.3 mg/kg, the 5-HT3 receptor antagonist ondansetron 0.03 mg/kg and the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) 0.01 mg/kg. Ifenprodil 10 mg/kg mimicked the alpha1-adrenoceptor antagonist prazosin 1 mg/kg in that it prolonged the hypnotic response to ethanol (no additive effect when both drugs were given in combination); this is compatible with an involvement of alpha1-adrenoceptors in this effect of ifenprodil. Chronic exposure to ethanol (7%) induced physical dependence. The severity of ethanol withdrawal was suppressed by ifenprodil 1 and 10 mg/kg. In conclusion, ifenprodil influences ethanol-related changes in mouse behaviour and may prove to be useful in the treatment of alcoholism.

Topics: Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Male; Mice; Piperidines; Prazosin; Seizures; Sleep; Substance Withdrawal Syndrome

To characterize the time course of the behavioral and biochemical aspects of the cannabinoid withdrawal syndrome, we injected the cannabinoid antagonist SR141716A (5 mg/kg i.p.) in rats made tolerant to CP-55,940 (0.4 mg/kg i.p., twice daily for 6.5 days), 1, 24 and 96 h after the last CP-55,940 injection. Because the CB1 receptor and G protein alpha subunit are involved in cannabinoid tolerance, we observed their changes throughout the brain during the withdrawal syndrome by use of in situ hybridization. In vehicle-pretreated rats SR141716A per se induced abnormal behavior significantly different from the vehicle group: wet dog shakes, forepaw fluttering and scratching. These signs remained significantly elevated even after the second and third antagonist doses. SR141716A significantly modified the mRNA levels of G alpha s and G alpha i subunits in some brain areas without affecting CB1 receptor and G alpha o expression. These findings led us to conclude that SR141716A may have intrinsic activity. Concerning cannabinoid withdrawal, the first SR141716A injection in tolerant rats resulted in behavioral signs different from those observed with the antagonist alone; this moderate withdrawal syndrome was characterized by turning, chewing and digging. Additional SR141716A doses 24 and 96 h later did not induce a significant abstinence syndrome. In situ hybridization after the first SR141716A injection showed that CB1 receptor and G protein alpha subunits, whose levels were low in tolerance, recovered their basal level of expression. Thus, the general desensitization of the cannabinoid receptor and of the transduction system in tolerance are recovered in abstinent rats and might be part of the molecular mechanisms underlying cannabinoid dependence.

Topics: Animals; Behavior, Animal; Cannabinoids; GTP-Binding Proteins; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; RNA, Messenger; Substance Withdrawal Syndrome

The present study investigated the effects of the NMDA receptor antagonists dizocilpine (MK-801) and ifenprodil on the appearance of diazepam withdrawal signs caused by discontinuation of long-term diazepam treatment using a drug-admixed food (DAF) method in Fischer 344 rats. The total withdrawal score was significantly decreased by after-withdrawal treatment with dizocilpine or ifenprodil. Dizocilpine, in particular, markedly suppressed the motor withdrawal signs and body weight loss, while ifenprodil suppressed the motor and emotional withdrawal signs. Furthermore, the decrease in the food intake during withdrawal (anorexia) was significantly reduced by dizocilpine, but not by ifenprodil. These behavioral results indicated that the activation of NMDA receptors during withdrawal may play an important role in the appearance of withdrawal signs (in particular motor withdrawal signs) caused by discontinuation of chronic diazepam treatment, and that inhibitory agents for NMDA receptors may be effective in alleviation of the appearance of benzodiazepine withdrawal signs.

Topics: Administration, Oral; Animals; Anorexia; Anti-Anxiety Agents; Behavior, Animal; Diazepam; Dizocilpine Maleate; Eating; Emotions; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Time Factors; Weight Loss

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta9-tetrahydrocannabinol (Delta9-THC) twice a day for 1 wk. SR141716A administration after the last Delta9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta9-THC regimens tested, daily Delta9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.

Topics: Analysis of Variance; Animals; Antiemetics; Appetite Stimulants; Behavior, Animal; Dronabinol; Hallucinogens; Male; Mice; Mice, Inbred ICR; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Cannabinoids; Dogs; Dronabinol; Endocannabinoids; Female; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome; Time Factors

Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide. HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated physical dependence on THC [Delta9-tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Endocannabinoids; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Substance Withdrawal Syndrome; Substance-Related Disorders

Recent reports have provided evidence of a link between the endogenous brain cannabinoid system and the endogenous central opioid systems. Here we report that the selective CB1 receptor antagonist SR 141716A induced behavioral and endocrine alterations associated with opiate withdrawal in morphine-dependent animals in a dose-dependent manner and that naloxone induced an opiate withdrawal syndrome in animals made cannabinoid-dependent by repeated administration of the potent cannabinoid agonist HU-210. Additionally CB1 and mu-opioid receptor mRNAs were co-localized in brain areas relevant for opiate withdrawal such as the nucleus accumbens, septum, dorsal striatum, the central amygdaloid nucleus and the habenular complex. These results suggest that CB1 cannabinoid receptors may play a role in the neuroadaptive processes associated with opiate dependence, and they lend further support for the hypothesis of a potential role of cannabinoid receptors in the neurobiological changes that culminate in drug addiction.

Topics: Animals; Brain Chemistry; Gene Expression; In Situ Hybridization; Male; Morphine Dependence; Naloxone; Narcotic Antagonists; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid, mu; Rimonabant; RNA, Messenger; Substance Withdrawal Syndrome

Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.

Topics: Analysis of Variance; Animals; Body Temperature; Body Weight; Conditioning, Psychological; Cyclic AMP; Dronabinol; Drug Interactions; Hallucinogens; Hypothermia; In Vitro Techniques; Male; Mice; Motivation; Narcotics; Pain Measurement; Piperidines; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraperitoneal; Injections, Subcutaneous; Kynurenic Acid; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

Corticotropin-releasing factor (CRF) has been implicated in the mediation of the stress-like and negative affective consequences of withdrawal from drugs of abuse, such as alcohol, cocaine, and opiates. This study sought to determine whether brain CRF systems also have a role in cannabinoid dependence. Rats were treated daily for 2 weeks with the potent synthetic cannabinoid HU-210. Withdrawal, induced by the cannabinoid antagonist SR 141716A, was accompanied by a marked elevation in extracellular CRF concentration and a distinct pattern of Fos activation in the central nucleus of the amygdala. Maximal increases in CRF corresponded to the time when behavioral signs resulting from cannabinoid withdrawal were at a maximum. These data suggest that long-term cannabinoid administration alters CRF function in the limbic system of the brain, in a manner similar to that observed with other drugs of abuse, and also induces neuroadaptive processes that may result in future vulnerability to drug dependence.

Topics: Amygdala; Animals; Anxiety; Behavior, Animal; Brain; Corticosterone; Corticotropin-Releasing Hormone; Dronabinol; Male; Microdialysis; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

In morphine-dependent rats pretreated with an intrathecal injection of saline (vehicle), intraarterial injection of 0.5 mg/kg of naloxone produced an immediate increase in blood pressure. Heart rate increased in most rats just after naloxone injection; however, the responses were transient, not lasting more than about 4 min after injection. Naloxone-precipitated behavioral changes were dominated by the appearance of body shakes and escape attempts that were strongly expressed during the first 10 min after naloxone. Pretreatment of morphine-dependent rats with an intrathecal injection of 100 nmol of the neurokinin-1 receptor antagonist CP-99994 significantly inhibited the magnitude and shortened the duration of the pressor response to naloxone. CP-99994 did ot reduce the expression of the associated withdrawal behaviors. Substance P significantly reversed the inhibitory effects of CP-99994 on the expression of the withdrawal-associated pressor response. Intrathecal pretreatment with CP-99994 also produced a dose-dependent inhibition of the expression of the pressor response to local spinal (intrathecal) injection of naloxone (60 micrograms) in morphine dependent rats without significant alteration of the expression of withdrawal-associated behaviors. These results indicate that spinal neurokinin-1 receptors mediate some of the cardiovascular signs of morphine withdrawal and suggest the possibility of developing a novel class of antiopiate withdrawal agents.

Topics: Animals; Injections, Spinal; Male; Morphine; Naloxone; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Substance Withdrawal Syndrome

A cannabinoid antagonist, SR 141716A, dose dependently precipitated a behavioral withdrawal syndrome in rats continuously infused i.p. for only 4 days with relatively low-dose regimens of delta 9-tetrahydrocannabinol. The following dose regimens, expressed as mg/kg/24 hr, were used for days 1 through 4: high-12.5, 25, 50 and 100; medium-2.5, 5, 10 and 20; and low-0.5, 1, 2 and 4. The major withdrawal signs of the syndrome were scratching, rubbing face with paws, licking, wetdog shakes, arched back and ptosis (at least 50% closure of eyelids). At the highest dose regimen, other signs noted in fewer subjects were biting, tongue rolling, retropulsion, head shakes, extended limbs or high stepping, ataxia, myoclonic spasms and front paw treading. During abrupt withdrawal (delta 9 tetrahydrocannabinol was discontinued and vehicle substituted) abstinence signs were also noted; however, except during a 48-hr observation period, withdrawal was not sufficiently robust to achieve statistical significance. The results of this study provide evidence that a modest course of delta 9-tetrahydrocannabinol can produce physical dependence. Hence, the risk and incidence of marijuana dependence in humans may be greater than previously projected.

Topics: Animals; Body Weight; Dronabinol; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome

Precipitated withdrawal in rats chronically exposed to delta 9-tetrahydrocannabinol, the major psychoactive principle of the marijuana plant, was unequivocally demonstrated for the first time using a selective antagonist, SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4- dichloro-phenyl)-4-methyl-1H-pyrazole carboxamide.HCl). This demonstration should provide a powerful stimulus for the systematic study of dependency on the psychoactive cannabinoids.

Topics: Animals; Dronabinol; Male; Piperidines; Psychotropic Drugs; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Anxiety; Benzodiazepines; Confusion; Female; Humans; Isoxazoles; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clonazepam; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoxazoles; Lorazepam; Piperidines; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

In September 1994, the National Institute of Mental Health convened a group of scientists to discuss the clinical effects of rapid clozapine discontinuation, especially in light of the introduction of risperidone for the treatment of schizophrenia. Despite concern over recent reports of clinical deterioration (psychotic exacerbations, somatic withdrawal symptoms, and extrapyramidal side effects) in a few patients abruptly discontinued from clozapine, there is currently insufficient information to determine the magnitude of the problems associated with clozapine withdrawal. However, clinicians are reminded that the withdrawal schedule for clozapine indicates a gradual tapering schedule (unless the patient is experiencing severe side effects); that switching patients from clozapine to risperidone does not mean that such tapering is unnecessary; and that the use of risperidone may not produce all of the same effects as clozapine in some treatment-refractory patients.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; United States; United States Food and Drug Administration

Tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was produced in rats by twice daily injections (15 mg/kg i.p.) for 6.5 days. Administration of the cannabinoid antagonist SR141716A (i.p. or i.c.v.) induced a profound precipitated withdrawal syndrome in delta 9-THC-tolerant animals. The syndrome was characterized by a disorganized pattern of constantly changing brief sequences of motor behavior. Autonomic signs were not evident. THC-tolerant animals that were treated with vehicle remained quiet throughout the observation period.

Topics: Animals; Behavior, Animal; Dronabinol; Hallucinogens; Injections, Intraperitoneal; Motor Activity; Piperidines; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome; Vocalization, Animal

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dystonia; Humans; Isoxazoles; Male; Neurologic Examination; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Previous studies in this laboratory have demonstrated that prior intracerebroventricular (i.c.v.) administration of the muscarinic antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) in morphine dependent rats significantly attenuates the development of cardiovascular and certain behavioral responses precipitated by the opiate antagonist, naloxone. The purpose of this study was to determine whether both supraspinal and spinal cholinergic neurons are involved in the expression of withdrawal symptoms. Employing localized (i.c.v. or intrathecal, i.t.) infusions of muscarinic antagonists, it was determined that a significant antiwithdrawal action could be produced through both an inhibition of supraspinal and spinal cholinergic neurons. Pharmacological difference emerged regarding the antiwithdrawal potential of 4-DAMP and the partially M1 selective antagonist, pirenzepine. While our previous studies had revealed that pirenzepine had essentially no antiwithdrawal activity when administered by the i.c.v. route, in the present study, pirenzepine evoked a marked antiwithdrawal action by the i.t. route, significantly inhibiting both cardiovascular and behavioral signs of withdrawal. In contrast, 4-DAMP which was effective by the i.c.v. route (especially for the cardiovascular symptoms), elicited no antiwithdrawal action by the i.t. route. As a muscarinic antagonist (ability to block the pressor response to central injection of carbachol) 4-DAMP was equally active by i.c.v. or i.t. injection. However, pirenzepine was clearly more effective in this regard by the i.t. route. These results are consistent with ability of muscarinic antagonists to offer significant anti-morphine withdrawal activity at both supraspinal and spinal locations. They also suggest that different muscarinic systems, possibly different receptor subtypes, mediate the expression of morphine withdrawal symptoms within the two regions of the CNS.

Topics: Animals; Blood Pressure; Cerebral Ventricles; Heart Rate; Injections, Intraventricular; Injections, Spinal; Male; Morphine; Muscarinic Antagonists; Naloxone; Piperidines; Pirenzepine; Rats; Rats, Wistar; Receptors, Muscarinic; Spinal Cord; Substance Withdrawal Syndrome; Time Factors

Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.

Topics: Amphetamine; Animals; Cocaine; Corpus Striatum; Dizocilpine Maleate; Dopamine; Ethanol; Male; Morphine; Naloxone; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Thiofentanil is a synthetic analgesic with pharmacological effects similar to etorphine hydrochloride (M99). The aim of the present study was to assess its analgesic and immobilization effects and to evaluate its dependence potential in comparison with morphine. The median analgesic dose (AD50) was measured by hot plate method in mice. The median paralytic dose (PD50), as an indicator of immobilization, was tested in rats, rabbits, dogs and monkeys. Results showed that the analgesic potency of this drug was 3260 times that of morphine, 22 times that of fentanyl and 1.5 times that of M99 and the immobilization effect was 2-3 times that of M99. Results from jumping test in mice and physical dependence-producing test in rats (the drug was dissolved in drinking water) showed that thiofentanil possessed physical dependence liability weaker than morphine. Physical dependence was not observed in rats with intravenous injection of one dose each h over a period of 72 h, and also in monkey with 20-week drug medication. The LD50 of thiofentanil was also determined in mice, rats, rabbits, dogs and monkeys in comparison with M99. Results suggest that it should be valuable to develop thiofentanil as an analgesic for clinical use.

Topics: Analgesics, Opioid; Animals; Dogs; Female; Immobilization; Macaca mulatta; Male; Mice; Pain; Piperidines; Rabbits; Rats; Sensory Thresholds; Substance Withdrawal Syndrome; Substance-Related Disorders; Thiazoles

It has been recognized for many years that central cholinergic neurons are susceptible to inhibition by opiates and that during withdrawal their firing rates are enhanced. Nevertheless, classical nonselective muscarinic receptor antagonists have not been demonstrated to provide consistent inhibition of withdrawal symptoms in humans or in animal models. The purpose of this study was to determine whether selective blockade of central M1 or M2 muscarinic receptor subtypes could provide inhibition of naloxone precipitated withdrawal symptoms in morphine dependent rats. As with earlier human studies, both cardiovascular and behavioral measures of withdrawal were quantitated. The selective M2 receptor antagonist 4-DAMP was significantly more effective than the M1 antagonist pirenzepine in reducing both cardiovascular and behavioral symptoms. These results are consistent with a role for cholinergic neurons in the expression of certain morphine withdrawal symptoms and suggest that future therapies might be targeted towards central M2 receptors.

Topics: Animals; Hemodynamics; Morphine; Muscarinic Antagonists; Naloxone; Parasympatholytics; Piperidines; Pirenzepine; Rats; Substance Withdrawal Syndrome

A quasi-morphine withdrawal syndrome (QMWS), produced in opiate-naive rats with an injection of isobutylmethylxanthine (IBMX) and the opioid antagonist naloxone, allows one to study the expression of opiate withdrawal in the absence of the acute or chronic effects of opiates and the adaptive processes termed dependence. The allegedly selective and long-acting serotonin2 (5-HT2) antagonist ritanserin attenuated the QMWS-induced suppression of fixed ratio (FR) operant responding, which is a sensitive measure of the expression of a QMWS. When administered 30 min prior to precipitation of the QMWS, the lowest dose of ritanserin tested (0.158 mg/kg) was the most effective in blocking the expression of withdrawal; however, there was not complete reversal of the behavioral suppression. Acutely, the two higher doses of ritanserin tested (2.5 and 10 mg/kg) suppressed responding when given alone. This may have masked their ability to attenuate a QMWS. At a dose of 2.5 mg/kg, ritanserin completely blocked the QMWS-induced suppression of responding 24 h post-administration, at a time when its actions at other receptors (e.g., alpha 2) have dissipated. At an equivalent dose, the shorter-acting 5-HT2 antagonist mianserin was unable to attenuate the QMWS-induced suppression of FR operant responding 24 h post-administration. The 5-HT2 antagonists reportedly produce a paradoxical down-regulation of 5-HT2 binding sites upon chronic treatment, rather than the expected supersensitivity. Chronic treatment with ritanserin (2.5 mg/kg/day for 7 days), but not mianserin (same regimen), attenuated a QMWS 24 h after the final injection, thus supporting with a functional measure, the down-regulation of such binding sites by ritanserin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; Animals; Conditioning, Operant; Male; Mianserin; Morphine Dependence; Naloxone; Piperidines; Rats; Reinforcement Schedule; Ritanserin; Serotonin Antagonists; Substance Withdrawal Syndrome

Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.

Topics: 1-Methyl-3-isobutylxanthine; 5-Hydroxytryptophan; Animals; Fluoxetine; Male; Methysergide; Mianserin; Morphine; Piperidines; Rats; Serotonin; Serotonin Antagonists; Substance Withdrawal Syndrome

Nine subjects who believed themselves to be poor sleepers, of mean age 58 years, took a placebo for 7 days, then ritanserin 5 mg for 20 days, followed by 3 days on placebo. Sleep was recorded electrophysiologically on 2 nights during baseline, 2 early drug nights, 2 late drug nights and the 2nd and 3rd withdrawal nights. Ratings of sleep quality were collected each morning. Ritanserin, a 5HT2 antagonist, caused a persistent doubling of the amount of EEG slow wave sleep, without altering the total duration of sleep. Ritanserin decreased the frequencies of awakening and after about a week it appeared to improve the subjective quality of sleep. Sleep was then impaired during withdrawal, as indicated by decreased duration and poorer subjective quality, being worst on the 3rd withdrawal night.

Topics: Attention; Electroencephalography; Female; Humans; Male; Middle Aged; Piperidines; Ritanserin; Serotonin Antagonists; Sleep; Sleep Stages; Sleep Wake Disorders; Substance Withdrawal Syndrome; Wakefulness

Several excitatory amino acid antagonists were tested for an ability to prevent spontaneous convulsions seen during the barbital abstinence syndrome in rats. Barbital-dependent animals were continuously infused intracerebroventricularly (i.c.v.) for the first 48 h following barbital withdrawal with either saline, 2-amino-7-phosphonoheptanoic acid (APH), magnesium sulfate, glutamyldiethyl ester (GDEE) or cis-2,3-piperidine dicarboxylic acid (PDA) using the highest dosages which did not affect normal behavior of the rats. All animals were observed continuously from 12 to 48 h postwithdrawal and the number of spontaneous convulsions observed in each animal was recorded. After this time, animals were killed by focused microwave irradiation and the cerebellas were collected for determination of cyclic guanosine monophosphate (cGMP) levels. While both APH and MgSO4 dramatically prevented convulsions, only APH prevented the withdrawal-induced elevation of cerebellar cGMP. PDA and GDEE had no statistically significant effect on either cerebellar cGMP levels or on convulsive activity. Although the effect of GDEE was not statistically significant, the number of convulsions was reduced to 1/3 those seen in control animals. These data implicate N-methyl-d-aspartate (NMDA) receptor-mediated pathways in seizure activity associated with the barbital abstinence syndrome and show that the withdrawal-induced elevation of cerebellar cGMP can occur without the induction of convulsions.

Topics: Amino Acids; Animals; Anticonvulsants; Barbital; Barbiturates; Dicarboxylic Acids; Female; Glutamates; Injections, Intraventricular; Magnesium Sulfate; Piperidines; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

We found 16 patients (15%) taking the anticholinergic biperiden because of its psychotropic action, occasionally, rather frequently or regularly, among a subgroup of 120 drug-dependent patients (drugs of the barbiturate and amphetamin types) out of a studied total of 194 imprisoned male addicts. These biperiden abusers suffered without exception from polytoxicomania associated with drug dependence and alcoholism. Most prominent was drug dependence on drugs of the morphine type. We could not prove a case of an isolated "primary" abuse of biperiden. Direct medical prescription was a rather secondary factor in procuring this preparation, in contrast to analgesics, tranquilisers, barbiturates and clomethiazol. Increase of biperiden abuse is due, on the one hand, to a generally noticeable tendency to polytoxicomania, and on the other hand to a change in Federal German drug prescription rules effective 1 August 1986 according to which fenetylline hydrochloride, a sympathomimetic, is now subject to medical prescription. Other centrally acting anticholinergics were unknown among this group of patients and were not abused. The results are discussed on the basis of available literature.

Topics: Adult; Biperiden; Dose-Response Relationship, Drug; Female; Humans; Male; Piperidines; Psychoses, Substance-Induced; Substance Withdrawal Syndrome; Substance-Related Disorders

The effects of two novel antitussive compounds, vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) and N-(2,4-dimethyl-6-methoxyphenyl)-4-(diethylamine)butanamide hydrochloride (OR K-269-HCl) on the suppression of withdrawal signs (hypothermia and weight loss) induced by repeated morphine administration were compared to those of acute morphine and codeine administrations. Moreover, spontaneous and precipitated withdrawal-induced hypothermia, weight loss and behavioural changes from repeated codeine, vadocaine and OR K-269-HCl administrations were studied. Acute administration of morphine clearly reversed the hypothermia and weight loss induced by spontaneous withdrawal from morphine. Codeine was not able to suppress the hypothermia and weight loss induced by morphine withdrawal. Acute injections of vadocaine and OR K-269-HCl did not alter these withdrawal signs either. Moreover, acute administration of codeine tended to prevent the weight loss induced by codeine withdrawal and caused behavioural changes. Spontaneous or precipitated withdrawal from repeated vadocaine or OR K-269-HCl administration caused neither hypothermia, weight loss nor behavioural changes. These results support the view that compounds vadocaine and OR K-269-HCl are free from morphine-like addictive properties.

Topics: Animals; Antitussive Agents; Behavior, Animal; Body Temperature; Body Weight; Codeine; Female; Mice; Morphine; Piperidines; Substance Withdrawal Syndrome; Substance-Related Disorders

The involvement of serotonin2 (5-HT2) receptors in the expression of opiate withdrawal was examined using a behavioral test for acute morphine dependence. The 5-HT2 antagonists, ketanserin and pirenperone, injected shortly before naloxone, attenuated the naloxone-induced suppression of an autoshaped lever-touch response in rats treated 4 h earlier with a moderate dose of morphine. A low dose of pirenperone was also effective in blocking withdrawal-induced hypothermia. These data support the hypothesis that 5-HT is involved in the expression of opiate withdrawal.

Topics: Animals; Body Temperature; Conditioning, Operant; Ketanserin; Male; Morphine Dependence; Piperidines; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.

Topics: Animals; Behavior, Animal; Benzomorphans; Buprenorphine; Butorphanol; Codeine; Discrimination, Psychological; Humans; Macaca mulatta; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Narcotic Antagonists; Pentazocine; Piperidines; Substance Withdrawal Syndrome

Prostaglandins and cyclic adenosine monophosphate have been claimed to play a major role in the morphine withdrawal syndrome, but intestinal secretion has not been ruled out as being responsible, at least in part, for the accompanying diarrhea. Therefore, experiments were performed in which the effect of naloxone-induced morphine withdrawal on jejunal and on colonic fluid transport was assessed in tied-off loops of rat intestine in vivo simultaneously with mucosal cyclic adenosine monophosphate levels or colonic luminal release of prostaglandin E2 or 5-hydroxytryptamine. Naloxone-induced withdrawal reversed fluid absorption to secretion without changing cyclic adenosine monophosphate levels, but markedly enhanced local prostaglandin E2 and 5-hydroxytryptamine release (p less than 0.01). Indomethacin and the 5-hydroxytryptamine receptor antagonist ketanserin prevented withdrawal-induced fluid secretion and the increase in prostaglandin E2 release without influencing the release of 5-hydroxytryptamine. In addition, the alpha 2-adrenergic receptor agonist clonidine promoted absorption during withdrawal, whereas atropine failed to influence fluid transport. These data suggest that naloxone-precipitated intestinal fluid secretion may contribute to diarrhea due to morphine withdrawal and that 5-hydroxytryptamine may play an important role in mediating this secretion through stimulation of local prostaglandin formation.

Topics: Animals; Atropine; Clonidine; Colon; Cyclic AMP; Diarrhea; Dinoprostone; Female; Humans; Indomethacin; Ketanserin; Morphine Dependence; Naloxone; Piperidines; Prostaglandins E; Rats; Rats, Inbred Strains; Serotonin; Substance Withdrawal Syndrome

We compared the dependence liabilities of therapeutic doses of nufenoxole and loperamide. Ten subjects received 10 mg nufenoxole every 12 hr for 10 days, and 9 others received 4 mg loperamide every 12 hr for 10 days. On the eighth day of drug a sensitive single-blind intravenous naloxone challenge was used to assess dependence liability. After 0.2, 0.4, and 0.6 mg naloxone, pupillary constriction (0.618 to 0.540 cm, p less than 0.005) was measured in subjects receiving nufenoxole, whereas slight dilation (0.596 to 0.622 cm, p less than 0.05) was observed in those receiving loperamide. Trapezius electromyogram activity decreased by 30% for nufenoxole and 12% for loperamide. There were slight decreases in core and skin temperatures (0.06 degrees to 0.12 degrees) in both groups, partly attributable to experimental conditions. Changes in physiologic measurements after naloxone were similar in both groups and not of sufficient importance to suggest physical dependence liability for either loperamide or nufenoxole at the doses used.

Topics: Adult; Antidiarrheals; Body Temperature; Electromyography; Humans; Loperamide; Male; Naloxone; Oxadiazoles; Piperidines; Pupil; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: 5-Hydroxytryptophan; Amitriptyline; Animals; Behavior, Animal; Dibenzazepines; Humans; Male; Mianserin; Piperidines; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Administration, Oral; Animals; Behavior, Animal; Female; Haplorhini; Humans; Injections, Intravenous; Injections, Subcutaneous; Loperamide; Macaca mulatta; Male; Piperidines; Self Administration; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Aged; Humans; Male; Perhexiline; Piperidines; Polyradiculoneuropathy; Substance Withdrawal Syndrome

A single administration of ifenprodil at the doses of 100, 200 and 400 mg/kg (p.o.), and 50 and 100 mg/kg (i.m.) produced a moderate CNS depression in rats, such as, sedation, ptosis, systemic muscle relaxation and decrease in motor activity. These symptoms appeared dose-dependently and persisted for about 4 hours following administration. In a direct physical dependence test, 5 groups of rats were fed the ifenprodil-admixed food together with drinking water ad libitum for 24 hours daily for 53 approximately 103 days (mean ifenprodil intake, 43--240 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.5 vs. 1 mg/g food to 4 mg/g food. In the natural withdrawal following administration, no significant withdrawal signs were observed in any group. In a substitution test either for phenobarbital or morphine, no suppression of withdrawal signs during the period of cross-administration of ifenprodil and no maintenance of dependence were observed. In a physical dependence-producing test, the rats fed ifenprodil never manifested withdrawal signs such as diarrhea, "wet shakes", sudden loss of body weight as in the levallorphan precipitation test. Ifenprodil apparently has no physical dependence liability.

Topics: Animals; Body Weight; Central Nervous System; Depression, Chemical; Dose-Response Relationship, Drug; Eating; Humans; Isoxsuprine; Levallorphan; Male; Morphine Dependence; Piperidines; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Animals; Barbiturates; Dogs; Drug Synergism; Drug Tolerance; Humans; Mice; Piperidines; Piperidones; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Tosyl Compounds; Tranquilizing Agents; Triacetoneamine-N-Oxyl

Topics: Amines; Analgesics; Animals; Body Temperature; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Humans; Isomerism; Morphine; Piperidines; Pyridines; Spectrophotometry, Infrared; Stereoisomerism; Substance Withdrawal Syndrome; Tail

Topics: Amides; Analgesics; Animals; Cough; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Edema; Female; Fumarates; Hindlimb; Humans; Male; Motor Activity; Pain; Piperidines; Propionates; Pyridines; Respiration; Self Medication; Spasm; Substance Withdrawal Syndrome; Tail

Topics: Atropine; Female; Humans; Male; Piperidines; Substance Withdrawal Syndrome; Substance-Related Disorders; Tranquilizing Agents