piperidines and Alcoholism

Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4β2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism.

Topics: Alcohol Deterrents; Alcoholism; Animals; Azepines; Azetidines; Carbamates; Disease Models, Animal; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Isoflavones; Molecular Targeted Therapy; Patents as Topic; Piperidines; Pyridines; Synaptic Transmission

Alcoholism is a multifarious and ongoing disease tightly related to the amount of alcohol ingested, the drinking pattern, the history of alcohol drinking and the individual features, such as some genetic traits. Worldwide alcohol is the necessary cause of approximately 60 diseases and causes circa 2.5 million deaths every year. Studies show that alcohol interacts with brain neurotransmission in a complex manner. Dopaminergic, GABAergic, serotonergic, cholinergic and glutamatergic systems are all key participants in the action of ethanol on the brain. Furthermore, several neuropeptides, such as endogenous opioid peptides, substance P, corticotropin-releasing hormone, or the appetite-regulating peptides (eg., neuropeptide Y, ghrelin or orexin) also play a role in alcohol drinking. Treatment of alcohol use disorders (AUD) is based on the application of combined approaches, including pharmacological intervention directed to different molecular targets. Results, however, are variable, not always satisfactory, and not applicable to all stages and pathologies or to all patients. New strategies focused on the control of neuropeptide performance in the brain are being explored and may be an advance in the therapy of alcoholism. The application of treatments ad personam represents a challenge that currently stimulates research in different realms, including epidemiology, psychology, chemistry, biochemistry, cell biology and pharmacology. In this review the potential value and application of ligands that modulate the function of opioid and neurokinin-1 receptors in alcoholism therapy is analyzed.

Topics: Alcoholism; Animals; Humans; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Opioid Peptides; Piperidines; Receptors, Neurokinin-1; Receptors, Opioid; Substance P

The lack of satisfactory results of alcohol dependence treatment force us to search for new directions of research. Recent studies concentrate on endocannabinoid transmission. The results show an interplay between the endocannabinoid and dopaminergic signaling in activation of the limbic reward system. The mechanisms leading to development of dependence are very complex and poorly recognized. Endogenous cannabinoids seem to have an important role in the functioning of this system, both directly and indirectly affecting the level of different neurotransmitters. The effect of alcohol on the endocannabinoid system is also complex and involves changes at the molecular level. Experimental studies have demonstrated an important role of the CB1 receptors in the neurochemical mechanism of alcohol consumption and its regulation. SR141716 (rimonabant), a CB1 receptor antagonist, significantly lowers voluntary alcohol intake and motivation for its consumption in various experimental studies. Very encouraging results of preclinical studies were not completely confirmed in the clinical studies. However, further clinical studies are still necessary.

Topics: Alcohol Drinking; Alcoholism; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Humans; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

The present paper summarizes the results of a number of pharmacological studies implicating the cannabinoid CB(1) receptor in the neural circuitry regulating different alcohol-related behaviors in rodents. Specifically, cannabinoid CB(1) receptor antagonists--including the prototype, rimonabant--have been reported to suppress: (a) acquisition and maintenance of alcohol drinking behavior under the 2-bottle "alcohol vs water" choice regimen; (b) the increase in alcohol intake occurring after a period of alcohol abstinence (an experimental model of alcohol relapse); (c) alcohol's reinforcing and motivational properties measured in rats trained to perform a specific task (e.g., lever-pressing) to access alcohol; (d) reinstatement of extinguished alcohol-seeking behavior triggered in rats by a nicotine challenge or presentation of cues previously associated to alcohol availability (another model of alcohol relapse). Additional data indicate that the opioid receptor antagonists, naloxone and naltrexone, synergistically potentiate the suppressing effect of rimonabant on alcohol intake and alcohol's motivational properties in rats. Conversely, the two clinical studies conducted to date (one in alcohol-dependent individuals and one in nontreatment-seeking heavy alcohol drinkers) yielded less conclusive results. Unfortunately, the recent discontinuation--due to the occurrence of some psychiatric adverse effects--of all trials with cannabinoid CB(1) receptor antagonists apparently hinders further investigations on the potential of rimonabant in the treatment of alcohol dependence.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Disease Models, Animal; Humans; Models, Animal; Narcotic Antagonists; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Alcoholism; Animals; Depression; Humans; Piperidines; Pyrazoles; Rimonabant

Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB(1) receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data-synthetically reviewed in the present paper-suggest (a) the involvement of the cannabinoid CB(1) receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence.

Topics: Alcohol Drinking; Alcoholism; Animals; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Opioid; Recurrence; Rimonabant

Topics: Alcoholism; Animals; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Adolescent; Adult; Aged; Alcoholism; Antisocial Personality Disorder; Child; Dementia; Epilepsy; Female; Humans; Intellectual Disability; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Nitriles; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Alcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system-a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients.. In a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking.. OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.

Topics: Adult; Alcohol Drinking; Alcoholism; Attention; Cognition; Cognition Disorders; Craving; Dopamine; Dopamine Agents; Double-Blind Method; Emotions; Executive Function; Female; Humans; Impulsive Behavior; Male; Memory, Short-Term; Middle Aged; Piperidines; Reaction Time; Recognition, Psychology; Young Adult

This prospective, randomized, controlled, rater-blinded study investigated the effect of G protein-activated inwardly rectifying potassium (GIRK) channel inhibitor ifenprodil on alcohol use in patients with alcohol dependence.. The participants were 68 outpatients with alcohol dependence who were assigned to an ifenprodil group (administered 60 mg ifenprodil per day for 3 months) or control group (administered 600 mg ascorbic acid and calcium pantothenate per day for 3 months). The participants completed a questionnaire that included the frequency of alcohol drinking and presence of heavy drinking before the study period (time 1) and 3 months after the start of the study period (time 2). The alcohol use score was calculated using these two items.. Valid data were obtained from 46 participants (25 in the ifenprodil group and 21 in the control group). The alcohol use score at time 2 in the ifenprodil group was significantly lower than that in the control group after adjusting for the score at time 1 and some covariates. The intention-to-treat analysis of multiply imputed datasets indicated similar results. Group differences in the frequency of alcohol drinking were significant in the multiply imputed datasets but not in 46 participants. The ifenprodil group had a significantly lower rate of heavy drinking at time 2 than the control group.. This study found an inhibitory effect of ifenprodil on alcohol use in patients with alcohol dependence. The results support the hypothesis that GIRK channel inhibitors ameliorate alcohol dependence.. This trial was registered in the UMIN clinical trial registry (UMIN000006347).

Topics: Adult; Aged; Alcohol Drinking; Alcoholism; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Male; Middle Aged; Piperidines; Potassium Channel Blockers

Alcohol dependence is associated with a dysregulated dopamine system modulating reward, craving and cognition. The monoamine stabilizer (-)-OSU6162 (OSU6162) can counteract both hyper- and hypo-dopaminergic states and we recently demonstrated that it attenuates alcohol-mediated behaviors in long-term drinking rats. The present Phase II exploratory human laboratory study investigated to our knowledge for the first time the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals. Fifty-six alcohol dependent individuals were randomized to a 14-day-treatment period of OSU6162 or placebo after their baseline impulsivity levels had been determined using the Stop Signal Task. On Day 15, participants were subjected to a laboratory alcohol craving test comprised of craving sessions induced by: i) active - alcohol specific cues, ii) neutral stimuli and iii) priming - intake of an alcoholic beverage (0.20g ethanol/kg bodyweight). Subjective ratings of alcohol craving were assessed using the shortened version of the Desire for Alcohol Questionnaire and visual analog scales (VAS). OSU6162 treatment had no significant effect on cue-induced alcohol craving, but significantly attenuated priming-induced craving. Exploratory analysis revealed that this effect was driven by the individuals with high baseline impulsivity. In addition, OSU6162 significantly blunted the subjective liking of the consumed alcohol (VAS). Although the present 14-day-treatment period, showed that OSU6162 was safe and well tolerated, this exploratory human laboratory study was not designed to evaluate the efficacy of OSU6162 to affect alcohol consumption. Thus a larger placebo-controlled efficacyclinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence.

Topics: Adult; Alcoholism; Craving; Cues; Double-Blind Method; Female; Follow-Up Studies; Humans; Impulsive Behavior; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Retrospective Studies; Statistics, Nonparametric; Time Factors

Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system.. Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)).. The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score.. The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.

Topics: Adult; Alcoholism; Analgesics, Opioid; Behavior, Addictive; Benzamides; Dopamine; Fluorine Radioisotopes; Functional Neuroimaging; Humans; Limbic System; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Pyrrolidines; Radioligand Assay; Receptors, Dopamine D2; Receptors, Opioid, mu; Remifentanil; Severity of Illness Index

There is an extensive literature showing that the CB(1) cannabinoid receptor antagonist rimonabant (SR141716) decreases alcohol consumption in animals, but little is known about its effects in human alcohol drinkers.. In this study, 49 nontreatment-seeking heavy alcohol drinkers participated in a 3-week study. After a 1-week baseline, participants received either 20 mg/day of rimonabant or placebo for 2 weeks under double-blind conditions. During these 3 weeks, participants reported their daily alcohol consumption by telephone. Subsequently, they participated in an alcohol self-administration paradigm in which they received a priming dose of alcohol followed by the option of consuming either eight alcohol drinks or receiving $3.00 for each nonconsumed drink. Endocrine measures and self-rating scales were also obtained.. Rimonabant did not change alcohol consumption during the 2 weeks of daily call-ins. Similarly, the drug did not change either alcohol self-administration or endocrine measures during the laboratory session.. We conclude that the daily administration of 20 mg of rimonabant for 2 weeks has no effect on alcohol consumption in nontreatment-seeking heavy alcohol drinkers.

Topics: Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Alcoholism; Double-Blind Method; Female; Humans; Hydrocortisone; Male; Motivation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reward; Rimonabant; Self Administration

Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.

Topics: Adult; Alcoholism; Body Mass Index; Body Weight; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Secondary Prevention; Treatment Outcome

Topics: Alcoholism; Blood Pressure; Chronic Disease; Female; Humans; Hypertension; Ketanserin; Male; Piperidines

In a double-blind study in chronic alcoholics melperone (Buronil) was shown to significantly improve muscular and nervous tension, emotional lability, somatization, ability to sleep, anxiety, depression, paranoid ideation and presumed ability to work, but had no effect on alcoholic craving. The results received from three rating scales, and the theoretical aspects of alcoholism are discussed.

Topics: Adult; Alcoholism; Antipsychotic Agents; Butyrophenones; Clinical Trials as Topic; Double-Blind Method; Humans; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Surveys and Questionnaires

In a 2-wk randomized double blind study 60 chronic alcoholics were treated with either melperone (Buronil) or placebo. The patients were assessed daily using a scale including 4 items: tension, depression, craving and sleep. Statistically significant improvement was achieved in the placebo group only for "tension" and "sleep"; whereas, in the melperone group all four items improved significantly. Comparison between the groups revealed statistically significant superiority of melperone over placebo for the item "craving".

Topics: Adult; Alcoholism; Butyrophenones; Clinical Trials as Topic; Depression; Double-Blind Method; Humans; Male; Middle Aged; Piperidines; Placebos; Sleep; Surveys and Questionnaires

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

Alcohol use disorders (AUD) often co-occur with anxiety and depressive disorders, and anxiety often drives relapse during alcohol abstinence. Optimal AUD pharmacotherapies may thus need to target both excessive alcohol intake and elevated anxiety. (-)-OSU6162 (OSU) is a monoamine stabilizer that attenuates alcohol-mediated behaviors in both preclinical and clinical settings. However, OSU's effect on anxiety-like behavior following long-term drinking remains unknown. To this end, we utilized a genetic rat model that exhibits increased anxiety- and depression-like behaviors (Flinders Sensitive Line; FSL) and their controls (Flinders Resistant Line; FRL). Using the novelty suppressed feeding (NSF) test, we evaluated anxiety-like behaviors (1) at baseline, (2) following long-term voluntary drinking and after 24 h of alcohol deprivation, and (3) following OSU administration in the same animals. At baseline, FSL animals displayed significantly elevated anxiety-like characteristics compared to FRL. Compared to alcohol-naïve animals, long-term drinking significantly reduced anxiety-like behaviors in FSL, without any significant effects in FRL animals. Compared to vehicle, OSU administration significantly reduced anxiety-like behaviors in alcohol-naïve FSL and long-term drinking FRL animals. While there was no significant difference in alcohol intake between FSL and FRL, OSU attenuated alcohol intake in both strains. Conclusively, in addition to the compound's previously identified ability to suppress alcohol-mediated behaviors, OSU may also possess anxiolytic properties, warranting further clinical evaluation in both AUD and anxiety disorder settings.

Topics: Alcohol Abstinence; Alcohol Drinking; Alcoholism; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Depression; Disease Models, Animal; Ethanol; Male; Motor Activity; Movement; Piperidines; Rats

This hypothesis is that patients with anorexia nervosa (AN) demonstrate derangement in the histamine central nervous system. It might be possible to ameliorate these by careful use of histamine receptor antagonists targeting Histamine 1, 2, or 3 receptors. Histamine 3 receptors are exclusively present in the brain. Pitolisant is the only one agent currently available that targets these receptors. Pitolisant (brand name Wakix) was approved in the European Union, as a treatment for narcolepsy in March 2016.

Topics: Alcoholism; Animals; Anorexia Nervosa; Behavior, Animal; Brain; Central Nervous System; Dietary Fats; Endocannabinoids; Female; Hibernation; Hippocampus; Histamine; Histamine Antagonists; Humans; Male; Piperidines; Prader-Willi Syndrome; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Sex Factors

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

Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl-D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long-lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression.

Topics: Alcoholism; Alternative Splicing; Animals; Antidepressive Agents; Comorbidity; Depressive Disorder, Major; Ethanol; Exons; Gene Expression; Hippocampus; Male; Mice, Inbred C57BL; Models, Animal; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Transcriptome

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

Topics: Alcohol Drinking; Alcoholism; Animals; Basolateral Nuclear Complex; Central Nervous System Depressants; Choice Behavior; Ethanol; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Tissue Culture Techniques

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

Topics: Adrenergic alpha-1 Receptor Antagonists; Alcoholism; Amphetamine; Animals; Behavior, Animal; Cyproheptadine; Ethanol; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Piperidines; Prazosin; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists

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

The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.

Topics: Alcohol Drinking; Alcoholism; Animals; Behavior, Addictive; Conditioning, Operant; Drug-Seeking Behavior; Ethanol; Female; Piperidines; Rats; Receptors, Opioid, kappa; Recurrence; Reinforcement, Psychology; Self Administration; Tetrahydroisoquinolines

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

The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2.. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [³H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography.. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake.. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.

Topics: Alcohol Drinking; Alcoholism; Animals; Body Weight; Central Nervous System Depressants; Dopamine; Ethanol; Male; Mice; Mice, Knockout; Motor Activity; Neostriatum; Nucleus Accumbens; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Dopamine D2; Rimonabant; Synaptic Transmission; Time Factors; Up-Regulation

Topics: Alcoholism; Analysis of Variance; Asian People; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Haloperidol; Humans; Middle Aged; Outpatients; Paroxetine; Piperidines; Retrospective Studies; Risk; Secondary Prevention; Treatment Outcome

The present study was designed to investigate the possible effect of chronic alcohol intake on propofol and remifentanil requirements, which was determined by quantifying the 50% (EC(50) ) and 95% (EC(95) ) effective effect-site concentrations for propofol and remifentanil at loss of consciousness (LOC) and after a painful stimulus.. Thirty male patients (alcoholic group; n = 30) with chronic alcoholism and 30 patients (control group; n = 30) with a history of small alcohol intake were anaesthetized with propofol and remifentanil by target-controlled infusion. The predicted drug concentrations and Bispectral Index (BIS) values were recorded at LOC and after no response to painful stimuli.. The EC(50) and EC(95) of propofol at LOC in alcoholic group were 3.15 [95% confidence interval (CI), 2.77-3.37] and 4.05 (95% CI, 3.18-5.26) μg/ml, respectively, and those of the control group were 2.21 (95% CI, 1.92-2.86) and 3.04 (95% CI, 2.45-4.64) μg/ml, respectively. The EC(50) and EC(95) of remifentanil measured after no response to painful stimuli in the alcoholic group were 3.02 (95% CI, 2.70-3.38) and 4.98 (95% CI, 4.56-5.89) ng/ml, respectively, and those of the control group were 2.95 (95% CI, 2.68-3.33) and 4.86 (95% CI, 4.55-5.92) ng/ml, respectively. The EC(50) and EC(95) values of propofol at LOC in the control group were significantly lower than that of the alcoholic group.. These findings suggest that the induction dose requirements of propofol are increased in alcoholic patients anaesthetized with propofol and remifentanil administered by target controlled infusion.

Topics: Adult; Alcoholism; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Electroencephalography; Humans; Male; Middle Aged; Piperidines; Propofol; Receptors, GABA-A; Remifentanil

Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB(1) receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB(1) receptor significantly reduced the ethanol preference. Although the stimulation of the CB(1) receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB(1) receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB(1) -/- mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB(1) receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB(1) receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB(1) receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB(1) receptor may have therapeutic potential in the treatment of ethanol dependence.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Analgesics; Animals; Binding, Competitive; Brain; Cyclohexanols; Disease Models, Animal; Genetic Predisposition to Disease; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Rimonabant; Species Specificity

Endogenous cannabinoids and their receptors, CB1 receptors in particular, have been implicated in mediation of ethanol reinforcement. Previously, suppression of ethanol drinking by CB1 antagonists has been demonstrated in many experimental paradigms. However, the exact mechanism by which CB1 antagonists modulate ethanol drinking remains elusive. In the present study, we assessed the role of CB1 receptors within the key regions of the mesolimbic dopamine pathway, the nucleus accumbens (NAcc) and ventral tegmental area (VTA), in regulation of ethanol self-administration.. Adult male alcohol-prefer AA rats were trained to self-administer either 10% (w/v) ethanol or 0.1% (w/v) saccharin under an FR1 schedule during daily 30-minute sessions. Following stable baseline responding, rats were tested after systemic administration of the CB1 antagonist SR141716A (0 to 10 mg/kg) and the agonist WIN55,212-2 (0 to 2 mg/kg). Separate groups of rats were implanted with bilateral cannulas aimed at the NAcc or VTA, and tested after microinjections of SR141716A (0 to 3 microg) and WIN55,212-2 (0 to 5 microg) into the NAcc or VTA. The highest intracerebral doses were tested also in rats responding for a 0.1% saccharin solution.. SR141617A dose-dependently suppressed ethanol responding after systemic administration. Microinjections of SR141617A both into NAcc and VTA attenuated ethanol responding. In addition, intra-NAcc injections of SR141617A suppressed saccharin intake. Although low doses of systemically given WIN55,212-2 increased ethanol responding, no effects were seen after WIN55,212-2 microinjections into NAcc or VTA.. Bidirectional changes in ethanol self-administration by the systematically administered CB1 agonist and antagonist show that ethanol reinforcement is controlled by CB1 receptors in alcohol-preferring AA rats. Replication of the suppressive effects by CB1 antagonism in the NAcc and VTA suggests that endocannabinoids and their receptors mediate ethanol reinforcement through interaction with the mesolimbic dopamine pathway.

Topics: Alcohol Drinking; Alcoholism; Animals; Benzoxazines; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Male; Microinjections; Morpholines; Naphthalenes; Nucleus Accumbens; Piperidines; Pyrazoles; Rats; Rats, Inbred Strains; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Signal Transduction; Ventral Tegmental Area

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

Topics: Aged, 80 and over; Alcohol Drinking; Alcoholism; Alzheimer Disease; Cholinesterase Inhibitors; Compulsive Behavior; Donepezil; Female; Humans; Impulsive Behavior; Indans; Nootropic Agents; Piperidines

This study investigated the effect of the new CB1 cannabinoid receptor antagonist, SR147778, on ethanol preference in chronically alcoholized Wistar rats. In study 1, SR147778, at doses of 0.3, 1, or 10 mg/kg/day (mg/kg/d) intraperitonealy (ip), was administered during chronic pulmonary ethanol intoxication for 30 days. The rats were then exposed to a two-bottle choice (ethanol 10% v/v vs. water) for at least 30 days. Neither 0.3 nor 1 mg/kg/d had any effect on ethanol preference. In contrast, the high dose induced a significant transient increase in ethanol intake between days 6 and 10. In study 2, SR147778, at doses of 0.3, 1, or 10 mg/kg/d ip, was administered during the free-choice period after chronic alcoholization. Both ethanol preference and intake were significantly reduced only for 1 and 10 mg/kg/d. These results reinforce the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol. When these results are compared with those obtained with SR141716 (Rimonabant) on ethanol preference, we observed that (1) coadministration of 10 mg/kg/d SR147778 during chronic alcoholization induced a shorter transient increase of ethanol intake than Rimonabant and (2) SR147778 treatment during the free-choice period at doses of 1 and 10 mg/kg/d decreased ethanol intake more dramatically than SR141716 which, furthermore, continued for the duration of the free choice.

Topics: Alcoholism; Animals; Disease Models, Animal; Food Preferences; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sucrose

The endocannabinoid system is involved in a variety of effects of drugs of misuse, and blockade of the cannabinoid CB1 receptor by selective antagonists elicits marked reductions in opioid and alcohol self-administration. The present study was designed to extend our knowledge of the role of the cannabinoid CB1 receptor in the modulation of alcohol misuse vulnerability in rats. Accordingly, using nonselected Wistar rats and genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, we investigated the effect of the CB1 antagonist SR141716A on operant alcohol self-administration and on reinstatement of alcohol-seeking behavior by environmental conditioning factors. In addition, in situ hybridization studies in both strains were performed to measure cannabinoid CB1 receptor mRNA in different brain areas of these animals. Results showed that intraperitoneal administration of SR141716A (0.03, 1.0 and 3.0 mg/kg) markedly inhibits ethanol self-administration and conditioned reinstatement of ethanol-seeking behavior in both strains of rats. ED50 analysis showed significantly higher sensitivity (P < 0.05) to the effect of SR141716A in msP rats than in heterogeneous Wistar rats. In situ hybridization studies revealed that, compared with Wistar rats, msP animals have consistently greater cannabinoid CB1 receptor mRNA expression in a number of brain areas, including the frontoparietal cortex, caudate-putamen and hippocampus (CA1 and dentate gyrus areas). In conclusion, we provide clear evidence that blockade of CB1 receptors reduces both ethanol self-administration and conditioned reinstatement of alcohol-seeking behavior in rats. In addition, current pharmacological and neuroanatomical data suggest that an altered function of the CB1 receptor system exists between genetically selected alcohol-preferring msP rats and a heterogeneous animal population.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Conditioning, Operant; Dose-Response Relationship, Drug; Ethanol; Food; In Situ Hybridization; Male; Motor Activity; Piperidines; Pyrazoles; Rats; Rats, Mutant Strains; Rats, Wistar; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Self Administration

We present a case of anesthesia for electroconvulsive (ECT) therapy that was complicated by emetic sensitivity to etomidate, fragile ictal threshold, and mild pseudocholinesterase deficiency. The anesthetic was designed in this patient taking all his issues in consideration. The mild pseudocholinesterase deficiency necessitated a (50-75%) reduction in succinylcholine dosage, careful monitoring of the train of four, and postictal amnestic coverage to prevent paralysis upon waking. The significant emetic response to etomidate prompted substitution to propofol and preemptive ondansetron. Propofol significantly raised the ictal threshold but significantly reduced the postprocedural emesis. Eventually, this clinical challenge was resolved with adjunctive use of low-dose etomidate and remifentanil. This combination preserved the ictal parameters, providing patient comfort, good clinical response, and therapeutic efficacy. Although seizure duration and quality often are restored with hyperventilation and caffeine, this case necessitated a return to etomidate for the restoration of satisfactory ictal parameters. Although this effect of remifentanil has been described with methohexital, and etomidate with alfentanil, to the best of our knowledge, this is the first reported case of adjunctive remifentanil with etomidate for preserving ictal threshold. The outpatient course of ECT was thus completed with all psychiatric and anesthetic goals satisfied: adequate seizure quality and duration, no paralysis upon waking, no post-ECT nausea and vomiting, and patient satisfaction. Anesthesiologists should be aware of factors influencing the seizure duration and, keeping in mind the coexisting medical conditions of the patient, adjustments should be made to get the best possible outcome.

Topics: Adult; Alcoholism; Anesthesia; Anesthetics, Intravenous; Anxiety Disorders; Bipolar Disorder; Differential Threshold; Electroconvulsive Therapy; Etomidate; Humans; Male; Piperidines; Remifentanil

Current pharmacotherapies for alcohol dependence in humans (e.g., naltrexone, acamprosate) are meeting with only limited therapeutic success. The development of novel pharmacotherapies is urgently needed but is reliant upon the screening of large numbers of candidate "anticraving" drugs using appropriate animal models. The development of animal models is complex because (1) laboratory animals are often reluctant to consume large quantities of alcohol, (2) inducing a state of alcohol dependence, analogous to the human condition, may require many months of alcohol exposure, (3) concluding that a given drug selectively reduces alcohol craving requires very carefully controlled experiments, and (4) false positives and false negatives may result from the sometimes distinct physiology and psychology of the alcohol-addicted human and rat. To address some of these problems, our laboratory has recently developed the "beer model" of alcohol dependence and craving. Rats, like humans, have a prodigious appetite for beer and will drink much more beer than equivalent ethanol solutions in water. Beer consumption in rats leads to clear signs of intoxication, anxiety reduction, and signs of withdrawal when beer access is suddenly denied. We have found that beer craving in rats is selectively reduced by the cannabinoid receptor antagonist SR 141716 and the opioid receptor antagonist naltrexone. Combining these two drugs appears to have a synergistic anticraving effect. Other promising pharmacotherapies for the future are discussed.

Topics: Alcoholism; Animals; Baclofen; Beer; Behavior, Addictive; Cannabinoid Receptor Antagonists; Corticotropin-Releasing Hormone; Humans; Models, Animal; Naltrexone; Narcotic Antagonists; Neuropeptide Y; Piperidines; Pyrazoles; Rats; Receptors, Corticotropin-Releasing Hormone; Receptors, GABA-B; Research Design; Rimonabant

Topics: Aged; Alcohol Withdrawal Delirium; Alcoholism; Donepezil; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines

To study the potential role of dependence status on CB1-mediated blockade of ethanol self-administration.. We examined the effects of the cannabinoid antagonist SR141716A (0, 0.03, 0.3, and 3 mg/kg) on operant ethanol (10% v/v) self-administration in male Wistar rats that were made ethanol-dependent by chronic (14 d) exposure to ethanol vapor-chambers or exposed to air in identical vapor chambers.. Dependent animals responded more for ethanol than did air control nondependent rats. The acute administration of a 3 mg/kg dose of SR141716A almost suppressed ethanol self-administration only in ethanol dependent animals. However, operant responses for food were not affected by the administration of SR141716A.. These results further support that cannabinoid CB1 receptor blockade may have a potential utility for the treatment of alcoholism.

Topics: Alcoholism; Animals; Cannabinoids; Conditioning, Operant; Ethanol; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Self Administration; Substance-Related Disorders

Tiscornia and Dreiling (Physiopathogenic Hypothesis of Alcoholic Pancreatitis: Supranormal Ecbolic Stimulation of the "Pancreon" Units Secondary to the Loss of the Negative Component of Pancreas Innervation. Pancreas 1987;2:604-612.) proposed that hypertonicity of intrapancreatic cholinergic neurons provoked by chronic alcoholism may contribute to the pathogenesis of chronic pancreatitis (CP). In the present study, the validity of this hypothesis was investigated in humans by studying the effects of atropine, cisapride, and ethanol on the meal-stimulated secretion of pancreatic polypeptide (PP) and cholecystokinin (CCK) in healthy volunteers, heavy drinkers, and CP patients. In healthy volunteers, the early phase PP response (0-40 min) to a test meal was completely blocked by atropine, whereas it was augmented by cisapride, an enhancer of acetylcholine release from cholinergic nerves. The early phase PP response to a test meal was inhibited by ethanol in healthy volunteers, whereas, in heavy drinkers, the response was augmented and the inhibition by ethanol was abrogated. In CP patients, ethanol tended to enhance the early phase PP response. Ethanol did not affect the early phase CCK response to a test meal in any group, but it significantly enhanced the late phase CCK response (40-120 min) in CP patients. These results suggest that: (i) oral ethanol may inhibit the postprandial activation of the cholinergic neural pathway to the pancreas in healthy subjects, (ii) in heavy drinkers, postprandial cholinergic tone may be augmented and become resistant to the inhibition by ethanol, and (iii) the ethanol-induced increase in the postprandial CCK response in CP patients may play some role in the pathophysiology of this disease.

Topics: Adult; Alcoholism; Analysis of Variance; Atropine; Cholecystokinin; Chronic Disease; Cisapride; Ethanol; Humans; Male; Middle Aged; Pancreatic Polypeptide; Pancreatitis; Parasympathomimetics; Piperidines; Postprandial Period; Radioimmunoassay

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Brain; Drug Interactions; Ethanol; Excitatory Amino Acid Antagonists; Humans; Ion Channels; Motivation; Piperidines; Receptors, N-Methyl-D-Aspartate; Taurine

Ethanol (EtOH) administration is considered to elicit its reinforcing properties by stimulating dopaminergic (DA) transmission in the mesolimbic system. Accordingly, (EtOH) activates dopamine neuronal firing in the Ventro-Tegmental Area (VTA) and DA output in the nucleus accumbens. Concomitantly, EtOH reduces the firing rate of Pars Reticulata (PR) neurons which are thought to exert an inhibitory control over DA neurons. Further, chronic ingestion of EtOH produces tolerance to its sedative effects as to the depressant effect on PR neurons but no tolerance to the DA stimulating action. Moreover the NMDA antagonist MK-801, but not SL-820715, stimulates DA firing, suggesting that this effect is not a general characteristic of NMDA receptor antagonists and questioning the possibility that NMDA-receptor blockade may underlie EtOh-induced activation of DA-ergic transmission. The results indicate that activation of the mesolimbic DA tract is essential in the rewarding properties of EtOH and that neither GABA-ergic inhibition nor NMDA-receptor blockade by EtOH, are causally linked to the EtOH-induced activation of DA-ergic transmission.

Topics: Alcoholism; Animals; Aversive Therapy; Dizocilpine Maleate; Dopamine; Electrophysiology; Ethanol; gamma-Aminobutyric Acid; Glutamic Acid; Limbic System; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reward; Synaptic Transmission

Topics: Adult; Affect; Alcoholism; Humans; Male; Middle Aged; Piperidines; Ritanserin; Serotonin Antagonists; Sleep

The kinetic parameters of 3H-paroxetine binding and 3H-serotonin uptake were studied in platelets of alcoholic patients. There was no difference between alcoholic and non alcoholic subjects in 3H-paroxetine binding. When binding and 3H-serotonin uptake were studied, in the same plasma of the same subjects, the Vmax of serotonin uptake was increased in alcoholics. The data confirm the involvement of serotonin uptake system in alcohol dependence and suggest that serotonin uptake and paroxetine binding sites may be regulated independently in this pathology.

Topics: Adult; Alcoholism; Blood Platelets; Humans; Kinetics; Middle Aged; Paroxetine; Piperidines; Serotonin; Serotonin Antagonists

High affinity 3H-paroxetine binding was studied in human frontal cortex and hippocampus obtained from normal controls and alcoholics. On the basis of Scatchard analyses, a significant decrease in the maximal number of binding sites (Bmax) was found in the hippocampus of alcoholics (n = 8) as compared with that of controls (n = 10) (mean +/- SD = 63 +/- 35 vs. 114 +/- 70 fmoles/mg protein). There was no significant difference in the dissociation constants (Kd) between the two groups. The presumed effect of chronic alcohol abuse on 3H-paroxetine binding may be region-specific since no significant difference in either Bmax or Kd for 3H-paroxetine binding was found in the frontal cortex between normal controls and alcoholics. No significant correlation of 3H-paroxetine binding with age or postmortem interval was observed. The decrease in 3H-paroxetine binding in the hippocampus of alcoholics is probably indicative of reduced density of serotonergic nerve terminals either as a preexisting condition or as a result of neuronal damage caused by ethanol or the sequelae of alcoholism, such as nutritional deficiencies.

Topics: Adult; Aged; Alcoholism; Binding Sites; Cerebral Cortex; Data Interpretation, Statistical; Female; Hippocampus; Humans; Male; Middle Aged; Paroxetine; Piperidines; Serotonin Antagonists

The accumulation of inositol monophosphate (IP1) was measured after stimulation of 5-hydroxytryptamine2 (5-HT2) receptors on platelets from alcoholics and healthy controls. In controls, 5-HT induced a dose-dependent response with an EC50 = 2 x 10(-6) M and a maximal response at 10(-5) M. Ritanserin, a selective 5-HT2 antagonist, markedly reduced the accumulation. The IP1 formation after stimulation by 10(-5) M 5-HT was significantly impaired in platelets from alcoholics as compared to controls. This study indicates that the 5-HT2 receptor function is inhibited in alcoholics. It also illustrates the possibility of using IP1 formation in peripheral cells as a mean of studying receptor function in disease.

Topics: Adult; Alcoholism; Blood Platelets; Humans; Inositol Phosphates; Male; Middle Aged; Piperidines; Receptors, Serotonin; Ritanserin; Serotonin; Sugar Phosphates

Ketanserin is a pure antagonist of serotonin S2-receptors, in blood vessels, platelets and bronchial tissue. Ketanserin has been suggested as hypotensive drug in man, but it shows as well a specific activity on platelet aggregation. An increased incidence of hypertension, of unknown origin, has been found in patients with chronic alcoholism: hypotheses have been made upon an increased incretion of catecholamines and a greater sensitivity of blood vessels' receptors to their action. The data from the present study of eleven patients show that these subjects had an increased platelet activity and ketanserin administration was effective in allowing both the blood pressure levels and platelet activity to resume their normal range. This drug is thus suggested, for its pharmacological properties, as an elective medication for hypertensive patients with chronic alcoholism.

Topics: Adult; Alcoholism; Antihypertensive Agents; Blood Pressure; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Time Factors

Ketanserin is a pure and selective antagonist of serotonin S2-receptors in blood vessels, platelets and bronchial tissue. It antagonizes serotonin-induced vasoconstriction, bronchoconstriction and platelet aggregation, and indirectly it blocks platelet release reaction. Ketanserin has little or no effect on healthy subjects. Serotonin-induced or serotonin-potentiated platelet aggregation is inhibited in blood drawn from ketanserin-treated healthy volunteers. Oral or parenteral ketanserin treatment did not cause major changes in beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) plasma concentrations, when basic values were normal. Increased microaggregate formation was found in alcoholics and heavy drinkers. It was also found that beta-TG and PF4 levels were higher in these patients than in the controls. Ketanserin treatment tended to normalize these protein levels in such patients.

Topics: Adult; Alcoholism; beta-Thromboglobulin; Female; Humans; Ketanserin; Male; Middle Aged; Piperidines; Platelet Aggregation; Serotonin Antagonists

Topics: Alcohol Drinking; Alcoholism; Animals; Humans; Piperidines; Rats; Serotonin Antagonists

Topics: Aged; Alcoholism; Female; Humans; Liver; Male; Middle Aged; Necrosis; Perhexiline; Piperidines

Topics: Alcoholism; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Hallucinations; Humans; Male; Palmitic Acids; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Sulfonamides

Topics: Abreaction; Adult; Alanine Transaminase; Alcoholism; Aspartate Aminotransferases; Attitude; Benzene Derivatives; Blood Pressure; Dioxoles; Follow-Up Studies; Hematocrit; Humans; Leukocyte Count; Male; Middle Aged; Personality; Piperidines

Topics: Alcoholism; Alcohols; Aldehydes; Antidepressive Agents; Azepines; Barbiturates; Bromides; Chlordiazepoxide; Chlormethiazole; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Methaqualone; Neurotic Disorders; Phenothiazines; Piperidines; Propylene Glycols; Thioridazine; Tranquilizing Agents; Xanthenes

Topics: Alcohol Drinking; Alcoholism; Animals; Methylphenidate; Piperidines; Rats; Tranquilizing Agents

Topics: Alcoholism; Piperidines; Salts