dizocilpine-maleate and Substance-Related-Disorders

Topics: Animals; Brain; Cocaine; Conditioning, Psychological; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Humans; Motor Activity; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Substance-Related Disorders

Topics: Animals; Behavior; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Substance-Related Disorders

Topics: Animals; Dizocilpine Maleate; Humans; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Receptors, Phencyclidine; Substance-Related Disorders

Tramadol, an atypical μ-opioid receptor agonist, as a psychoactive drug, is frequently abused by human beings. Understanding the neurobiological mechanisms of drug-associated learning and memory formation may help prevent drug addiction and relapse. Previous study revealed that dorsal hippocampus (CA1) plays a crucial role in the retrieval of tramadol-associated memory and that its role depends on the expression of CA1 N-methyl-D-aspartate (NMDA) receptors (Jafari-Sabet et al. Can J Physiol Pharmacol 96:45-50, 2018).. To clarify the exact mechanisms involved, the activation of CA1 nitric oxide (NO) signaling pathway by L-arginine (a nitric oxide precursor) on the interaction between tramadol and MK-801 in memory retrieval was examined. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated and a single-trial step-down inhibitory avoidance apparatus was used for the assessment of memory retrieval.. Post-training and/or pre-test microinjection of tramadol (0.5 and 1 μg/mouse) and/or a non-competitive NMDA receptor antagonist, MK-801 (0.25 and 0.5 μg/mouse), induced amnesia which were reversed when the same doses of the drugs were administered 24 h later in a pre-test session, suggesting tramadol state-dependent learning (SDL) and MK-801 SDL. The amnesia induced by post-training microinjection of tramadol (1 μg/mouse) was reversed by pre-test microinjection of MK-801 (0.25 and 0.5 μg/mouse). Pre-test microinjection of MK-801 (0.125 and 0.25 μg/mouse) with an ineffective dose of tramadol (0.25 μg/mouse) potentiated tramadol SDL. The amnesia induced by post-training microinjection of MK-801 (0.5 μg/mouse) was reversed by pre-test microinjection of tramadol (0.5 and 1 μg/mouse). Pre-test microinjection of tramadol (0.25 and 0.5 μg/mouse) with an ineffective dose of MK-801 (0.125 μg/mouse) potentiated MK-801 SDL. Pre-test microinjection of ineffective doses of L-arginine (0.125, 025, and 0.5 μg/mouse) improved amnesia induced by the co-administration of tramadol and MK-801. Pre-test microinjection of L-arginine (0.125, 025, and 0.5 μg/mouse) could not reverse amnesia induced by post-training microinjection of tramadol while same doses of L-arginine improved MK-801 response on tramadol SDL.. The results strongly propose that activation of CA1 NO signaling pathway has a pivotal role in cross SDL among tramadol and MK-801.

Topics: Amnesia; Analgesics, Opioid; Animals; Arginine; CA1 Region, Hippocampal; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Learning; Male; Memory; Mice; Microinjections; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; Tramadol

Abuse of toluene-containing inhalants is common during adolescence, with ongoing chronic misuse associated with adverse outcomes and increased risk for addictive behaviours in adulthood. However, the mechanisms mediating the adaptive processes related to these outcomes are not well defined. To model human abuse patterns we exposed male adolescent Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1h/day, three times/week for 3 weeks. The effects of CIT on behaviour and recovery were monitored. Locomotor activity was recorded following two consecutive injections of amphetamine (1mg/kg, i.p.) 72 and 96 h after the last exposure. This was followed with injection of the NMDA receptor antagonist MK801 (0.5mg/kg, i.p.) 20 days after the last exposure. CIT resulted in a significant and persistent retardation in weight gain during the exposure period and abstinence (p<0.05). Repeated exposure resulted in tolerance to the onset of toluene-induced behaviours and recovery latency. There was a reduction in the acute stimulant effects of amphetamine in CIT-exposed animals and an increase in the magnitude of locomotor activity (p<0.0125) following a subsequent exposure when compared to the responses observed in controls; this was associated with altered locomotor responses to MK801. Repeated exposure to CIT during adolescence alters parameters of growth, as measured by body weight, and leads to tolerance, indicating that increasing concentrations of the compound may be needed to reach the same behavioural state. Toluene during this period also alters responses to a psychostimulant which may be related to long-term glutamatergic dysfunction.

Topics: Aging; Amphetamine; Animals; Central Nervous System Stimulants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Solvents; Substance-Related Disorders; Time Factors; Toluene; Weight Gain

The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern.. This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison.. Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency-rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2-10.0 mg/kg) and MK-801 (0.032-0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0 mg/kg/day) and acute cocaine (10.0 mg/kg).. Following acute administration, ketamine (3.2-10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032-0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS.. The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.

Topics: Anesthetics, Dissociative; Animals; Cocaine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Medial Forebrain Bundle; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Self Stimulation; Substance-Related Disorders; Time Factors

Although abuse of benzodiazepines alone is uncommon, it is high in polydrug abusers, including those who primarily use opioids or stimulants.. This study investigated whether drugs that are abused (e.g., amphetamine) or drugs that have mechanisms of action similar to abused drugs (e.g., morphine) alter the discriminative stimulus effects of the benzodiazepine midazolam.. Three rhesus monkeys discriminated 0.56 mg/kg of midazolam while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for midazolam alone and in the presence of morphine (opioid receptor agonist), amphetamine (dopamine receptor indirect agonist), dizocilpine (N-methyl-D: -aspartic acid receptor antagonist), or γ-butyrolactone (prodrug of γ-hydroxybutyrate, which acts primarily at GABA(B) receptors).. Doses of midazolam larger than 0.32 mg/kg produced ≥80% midazolam-lever responding. When administered alone, morphine, amphetamine, dizocilpine, and γ-butyrolactone did not produce midazolam-lever responding, although large doses of each drug eliminated responding; when administered in combination with midazolam, they did not alter the discriminative stimulus effects of midazolam up to doses that markedly decreased response rates.. The current study demonstrates a lack of modulation of the discriminative stimulus effects of midazolam by morphine, amphetamine, dizocilpine, and γ-butyrolactone. Other effects of benzodiazepines, such as their reinforcing effects, might be altered by these other drugs, or benzodiazepines might modulate the discriminative stimulus or reinforcing effects of the other drugs, which might contribute to the relatively high incidence of benzodiazepine abuse among polydrug abusers.

Topics: 4-Butyrolactone; Amphetamine; Animals; Codependency, Psychological; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Macaca mulatta; Male; Midazolam; Morphine; Reinforcement, Psychology; Substance-Related Disorders; Time Factors

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knockin mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1 (PP1), but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of PP1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.

Topics: Analysis of Variance; Animals; Anisomycin; Cocaine; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agonists; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Administration Routes; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Green Fluorescent Proteins; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Motor Activity; Narcotics; Point Mutation; Protein Synthesis Inhibitors; Raclopride; Receptors, Dopamine D1; Substance-Related Disorders; Threonine; Time Factors

An increase in polydrug abuse is a major problem worldwide. A previous study showed that coadministration of methamphetamine and morphine induced lethality in rodents and humans. However, the underlying mechanisms by which the lethality is increased by the coadministration of methamphetamine and morphine have not been fully understood. Therefore, the present study was designed to determine the mechanism of increased lethality induced by methamphetamine and morphine. Coadministered methamphetamine and morphine increased the lethality by more than 70% in BALB/c mice. Pretreatment with NMDA-receptor antagonists, such as MK-801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP), and benzamide [poly(ADP-ribose) polymerase (PARP) inhibitor] significantly attenuated the increased lethality induced by methamphetamine and morphine. Furthermore, the lethal effect induced by methamphetamine and morphine was completely attenuated by immediate cooling after the coadministration of methamphetamine and morphine. It has been reported that methamphetamine-induced neurotoxicity can be blocked by lowering the temperature, and this effect might be mediated by a reduction of release of free radicals. These results suggest that activation of NMDA receptors and PARP play an important role in the increased lethality induced by methamphetamine and morphine.

Topics: Animals; Behavior, Animal; Benzamides; Body Temperature; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Heart; Hypothermia, Induced; Liver; Male; Methamphetamine; Mice; Mice, Inbred BALB C; Morphine; Myocardium; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; Survival Rate; Time Factors

Heat shock proteins (HSP) such as HO-1 and HSP27 have been implicated as functioning in a protective manner against oxidative and physical stress. The objective of the current study was to determine the role of HSPs in drug-withdrawal stress induced in phenobarbital-dependent rats. Increased expression of HO-1 and HSP27 was observed in the hippocampus and the cerebral cortex of phenobarbital-withdrawn rats. Gene expression was measured by Northern and Western blot analyses and in situ hybridization. The induction of HO-1 mRNA was suppressed by the administration of the NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine (MK801). Despite significant upregulation of glutamatergic transmission, neuronal cell degeneration was not apparent. These findings suggest that the induction of HO-1 and HSP27 during withdrawal from phenobarbital dependence may play a role in protection against glutamate toxicity.

Topics: Animals; Anticonvulsants; Brain; Cell Survival; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Heat-Shock Proteins; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hippocampus; HSP27 Heat-Shock Proteins; In Situ Hybridization; Male; Neoplasm Proteins; Phenobarbital; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Substance Withdrawal Syndrome; Substance-Related Disorders

Opiate or NMDA receptor antagonists given during and/or after the development of tolerance and dependence have been reported to prevent these developments. In the present study, MK801 (dizolcipine) and naltrexone (NX), two antagonists of NMDA and opiate receptors, respectively were used in rats to find any correlations between changes in NMDA receptor kinetics, and the intensity of tolerance and dependence. Thus, six different groups of rats were formed. The rats in the groups were given saline (S)+S, S+morphine (M), NX+S, NX+M, MK801+S and MK801+M, respectively, once per day for 8 days. On day 9, the rats from each group were divided into four subgroups. The rats of the first subgroup were subjected to the determination of tail-flick latency. The rats of the second subgroup were administered 1 mg kg-1 naloxone (NL) 2 h after administration of 3 mg kg-1M. The rats of the third subgroup were implanted with two M pellets and after 72 h they were challenged with NL. The remaining rats received drugs also on day 9 according to the previous administration paradigm. Two hours after the administrations, their brains were utilised for the determination of NMDA receptor kinetics, employing [3H]glutamate. The measurement of tail-flick latency showed the prevention by NX or MK801 of the development of tolerance to M. The rats, which were administered 3 mg kg-1M 2 h before 1 mg kg-1 NL injection, on day 9 showed that only NX given previously along with M attenuated the intensity of the development of M dependence. NX administered alone intensified the development of dependence on a single dose of M. The development of M dependence upon the M pellet implantation was intensified by the previous administration of NX or MK801 concomitantly with M. The administration of M or MK801 alone, or NX together with M, caused significant upregulation of NMDA receptors. NX alone, and MK801 given concurrently with M led to a significant downregulation. So, in light of the previous findings and the present experimental data it can be said that: (1) supersensitivity to opioids may be a downregulation of NMDA as well as an upregulation of the opioid receptor; (2) either upregulation or downregulation of NMDA receptors may facilitate subsequent development of opioid dependence; (3) tolerance to opioid may necessitate both upregulation of NMDA receptors and downregulation of opioid receptors; and (4) beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS i

Topics: Analgesics, Opioid; Animals; Brain; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; Kinetics; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders

Topics: Animals; Conditioning, Psychological; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Rats; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior; Substance-Related Disorders

In three separate place conditioning experiments with rats, repeated access to novel objects in one of two distinct environments conditioned an increase in preference for the novelty-paired environment. A conditioned increase in preference was found whether novel objects were paired with a randomly chosen environment or with the less preferred of two environments (conditioned against a preference). This enhanced preference did not depend on the control group employed. Control groups exposed only to the place conditioning apparatus or to both the apparatus and the novel objects showed no systematic shift in place preference. Intravenous infusions of cocaine also produced an increase in preference using the procedures employed with novel objects. Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.03 mg kg(-1)) blocked acquisition of the enhanced place preference conditioned by access to novel objects without decreasing time spent with objects or inducing a place aversion in controls. Combined, these results show that access to novel objects can serve as an appetitive stimulus like drugs of abuse and that this novelty-induced appetitive process involves NMDA receptors. These place-conditioning procedures may provide a good model for determining the behavioral and neural process underlying the appetitive effects of novelty.

Topics: Animals; Appetite; Cocaine; Conditioning, Operant; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Environment; Excitatory Amino Acid Antagonists; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reward; Substance-Related Disorders

We evaluated the incentive motivational properties of MK-801 by determining its priming effect on drug-seeking behaviour following extinction of cocaine self-administration, an animal model for drug craving. Rats were allowed to self-administrate cocaine (0.5 mg/kg) or saline during 10 daily sessions. MK-801 (0.1-0.25 mg/kg, i.p.) dose-dependently reinstated responding for cocaine following an extinction period of 3 weeks. Responding was selectively enhanced in the previously drug-paired hole and was completely absent in rats with a history of saline self-administration. These data provide evidence for a possible role of NMDA receptors in the incentive motivation underlying cocaine-seeking behaviour. In addition, the ability of MK-801 to elicit drug-seeking behaviour may prove to be a serious drawback for the proposed use of NMDA antagonists in the treatment of drug addiction.

Topics: Analysis of Variance; Animals; Cocaine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Extinction, Psychological; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Self Administration; Substance-Related Disorders

Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 microgram) and MK-801 (5.0, 10.0, and 20.0 microgram) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure.

Topics: Amphetamine; Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Intake; Excitatory Amino Acid Antagonists; Food Deprivation; Locomotion; Male; Nicotine; Nicotinic Agonists; Phencyclidine; Rats; Rats, Sprague-Dawley; Reward; Self Administration; Substance-Related Disorders; Sympathomimetics

N-Methyl-D-aspartate (NMDA) antagonists induce psychotomimetic effects in humans that closely resemble negative and cognitive symptoms of schizophrenia. NMDA agonists, in contrast, may significantly ameliorate such symptoms. In rodents, phencyclidine (PCP) and other NMDA antagonists induce a hyperlocomotory syndrome that is reversed by NMDA agonists. The present study investigates the mechanism of action of glycyldodecylamide (GDA), a drug that is 80-fold more potent than glycine in reversing PCP-induced hyperactivity in rodents. At concentrations relevant to its behavioral actions, GDA significantly inhibits forebrain glycine uptake, indicating that glycine uptake inhibition may provide effective treatment for PCP psychosis and PCP psychosis-like symptoms of schizophrenia.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Hippocampus; In Vitro Techniques; Phencyclidine; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Phencyclidine; Schizophrenia; Substance-Related Disorders; Synaptosomes

We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Animal; Brain; Dizocilpine Maleate; DNA-Binding Proteins; GABA Modulators; Histocytochemistry; In Situ Hybridization; Kainic Acid; Male; Phenobarbital; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Receptors, Glutamate; RNA, Messenger; Substance Withdrawal Syndrome; Substance-Related Disorders; Transcription Factor AP-1

Effects of continuous pentobarbital administration on binding characteristics of [3H]MK-801 in the rat brain were examined by autoradiography. Animals were rendered tolerant to pentobarbital using i.c.v. infusion of pentobarbital (300 micrograms/10 microliters/hr for 7 days) by osmotic minipumps and dependent by abrupt withdrawal from pentobarbital. The levels of [3H]MK-801 binding were elevated in rats 24-hr after withdrawal from pentobarbital while there were no changes except in septum and anterior ventral nuclei in tolerant rats. For assessing the role of NMDA receptor in barbiturate action, an NMDA receptor antagonist (MK-801, 2.7 femto g/10 microliters/hr) was co-infused with pentobarbital. The pentobarbital-infused group had a shorter duration of pentobarbital-induced loss of righting reflex (sleeping time) than that of the control group, and MK-801 alone did not affect the righting reflex. However, co-infusion of MK-801 blocked hyperthermia, and prolonged the onset of convulsions induced by t-butylbicyclophosphorothionate (TBPS) in pentobarbital withdrawal rats. In addition, elevated [35S]TBPS binding was significantly attenuated by co-infusion with MK-801. These results suggest the involvement of NMDA receptor up-regulation in pentobarbital withdrawal and that the development of dependence can be attenuated by the treatment of subtoxic dose of MK-801.

Topics: Animals; Autoradiography; Cerebral Ventricles; Dizocilpine Maleate; Drug Evaluation, Preclinical; Drug Tolerance; Excitatory Amino Acid Antagonists; Infusion Pumps, Implantable; Male; Pentobarbital; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.

Topics: Animals; Bromocriptine; Buprenorphine; Cocaine; Desipramine; Diazepam; Dizocilpine Maleate; Hemodynamics; Male; Piperazines; Rats; Rats, Sprague-Dawley; Substance-Related Disorders

A series of experiments were conducted to investigate the role of dopaminergic D1 and D2 and glutamatergic NMDA and AMPA/kainate receptors on the establishment and expression of cocaine-induced conditioned locomotion in rats. In the first experiment conditioned locomotion was demonstrated by testing the animals in an environment previously associated with 15 mg/kg i.p. cocaine. The D2-receptor antagonist (-)-sulpiride (50 and 100 mg/kg i.p.) administered before cocaine during the conditioning phase did not modify the establishment of conditioned locomotion whereas when administered before testing only at the higher dose it partially reduced rats' locomotion in the absence of cocaine (expression). At the higher dose (0.1 mg/kg i.p.) the D1-receptor antagonist SCH 23390 attenuated the expression of cocaine-induced conditioned locomotion whereas the lower dose (0.03 mg/kg i.p.) had no effect. Both doses of the NMDA receptor antagonist MK-801 (0.125 and 0.25 mg/kg i.p.) blocked the development of cocaine-induced conditioned locomotion but neither dose, when administered before testing, modified locomotion in the absence of cocaine. Both doses of the AMPA/kainate receptor antagonist DNQX administered intracerebroventricularly (1 and 3 micrograms/rat) blocked cocaine-induced conditioned locomotion when given before cocaine during conditioning but when given before testing only the higher dose attenuated the conditioned activity. The results confirm the importance of the interaction between glutamatergic and dopaminergic systems for the conditional factors maintaining drug seeking behaviour. The findings may have implications for the treatment of cocaine craving and relapse.

Topics: Analysis of Variance; Animals; Benzazepines; Cocaine; Conditioning, Psychological; Dizocilpine Maleate; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Locomotion; Male; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Recurrence; Substance-Related Disorders; Sulpiride

Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (Ki, 2.3 microM at -60 mV). Consistent with this observation, ibogaine competitively inhibits [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (Ki, 1.5 microM) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 microM). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate the prototypic voltage-dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative "antiaddictive" property of this alkaloid, its ability to reduce the expression of morphine dependence.

Topics: Animals; Cerebellum; Dizocilpine Maleate; Electric Conductivity; Excitatory Amino Acid Antagonists; Hippocampus; Ibogaine; Male; Mice; Naloxone; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Substance-Related Disorders

The behavioral effects of phencyclidine (PCP) were studied in male and female Sprague-Dawley rats to determine if chronic infusions would result in sexually dimorphic effects. Rats were trained to make operant responses for food during 30-min response periods that occurred 4 times each day. After attaining stable baseline behaviors, 10 mg of PCP/kg/day was infused s.c. for 10 days. Females were more profoundly affected than males. In the females, response rates were suppressed to 30-71% of control rates during the first 7 days of infusion. In contrast, response rate in male rats never fell below 77% of control during the infusion period. By the eighth infusion day both sexes had become tolerant to these behavioral effects. After stopping infusions there was clear evidence that behavioral dependence had developed; however, the abstinence effects in males and females were similar. Saturation studies of [3H]dizocilpine (MK-801; (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) binding to brain membranes were conducted to determine if there were sex-dependent receptor differences. There were no significant differences in Kd +/- S.D. (7.6 +/- 1.5 and 7.1 +/- 0.9 nM for males and females, respectively) or Bmax +/- S.D. (4.1 +/- 0.2 and 4.0 +/- 0.5 pmol/mg protein for males and females, respectively).

Topics: Analysis of Variance; Animals; Behavior, Animal; Binding, Competitive; Brain; Computer Simulation; Dizocilpine Maleate; Female; Injections, Subcutaneous; Male; Phencyclidine; Rats; Rats, Sprague-Dawley; Sex Characteristics; Substance-Related Disorders

Rats were trained to respond under a fixed-ratio 30 schedule for food presentation during four daily 0.5-h sessions occurring every 6 h. After stable baseline response was established, osmotic minipumps were implanted that infused vehicle or (+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate (dizocilpine; MK-801), SC. Behavioral sessions continued to be conducted daily. After 10 days the infusion pumps were removed. Vehicle and 0.10 mg/kg per day MK-801 did not affect behavior during infusions or after cessation of dosing. Dosing with 0.32 and 0.56 mg/kg per day initially suppressed responding, but tolerance developed to these effects. After the infusions were stopped, a dose-dependent disruption of operant behavior occurred. Response rates for the 0.32 and 0.56 mg/kg per day infusion groups were suppressed to 41 and 27% of preinfusion control response rates, respectively, the day after dosing stopped; however, no physical signs of abstinence were observed. Response rates recovered toward control over the next 2-4 days. In a separate experiment, the suppression of response produced by abstinence from 0.32 mg/kg per day of MK-801 (SC) for 10.5 days was reversed by readministration of MK-801 (IP). These results demonstrate that MK-801 produces dependence, as evidenced by the emergence of a behavioral abstinence syndrome after cessation of dosing.

Topics: Animals; Body Weight; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Infusion Pumps, Implantable; Male; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Substance-Related Disorders

Both the antiepileptic, carbamazepine, and the N-methyl-D-aspartate receptor antagonist, dizocilpine, have shown preclinical efficacy against behavioral and toxic effects of cocaine. Nonetheless, side effects or toxicity of these compounds either alone or in conjunction with cocaine are problematic. 5-Aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5,1 0-imine (ADCI), a molecular hybrid of these compounds, has been shown to have a broad anticonvulsant profile with a good protective index (behavioral TD50/anticonvulsant ED50). In male Swiss Webster mice, ADCI and dizocilpine produced dose-dependent protection against the convulsant effects of cocaine that were insensitive to carbamazepine. However, in contrast to dizocilpine, ADCI did not produce behavioral impairment on the inverted screen test demonstrating a protective index of greater than 15; the protective index for dizocilpine was 1.2. All three compounds attenuated the locomotor stimulant effects of cocaine without significantly decreasing locomotor activity on their own, although the cocaine antagonism was not always dose dependent. Only dizocilpine increased spontaneous locomotor activity when given alone and augmented the locomotor stimulant effects of cocaine. The results confirm the novel anticonvulsant activity of ADCI and its lack of phencyclidine-like behavioral side effects. The data also suggest a modest blocking action of these compounds against the locomotor stimulatory effects of cocaine.

Topics: Animals; Anticonvulsants; Carbamazepine; Cocaine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice; Motor Activity; Receptors, N-Methyl-D-Aspartate; Seizures; Substance-Related Disorders

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

Topics: Analgesia; Animals; Behavior, Animal; Dizocilpine Maleate; Drug Tolerance; Male; Morphine; Naloxone; Pain Measurement; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders

Selective antagonists of the N-methyl-D-aspartate (NMDA) receptor such as MK-801 may have therapeutic potential in the treatment of ischemic brain injury. However, some drugs (e.g. ketamine and phencyclidine) with potent NMDA antagonist properties are also addictive. Intracranial self-stimulation (ICSS) is facilitated by drugs of abuse such as cocaine and amphetamine and thus is useful for screening compounds with potential abuse liability. Low doses of the NMDA antagonist, MK-801 were also found to facilitate ICSS, suggesting that this compound may possess abuse potential.

Topics: Animals; Anticonvulsants; Arousal; Brain; Dibenzocycloheptenes; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Self Stimulation; Substance-Related Disorders

We have used microelectrophoretic and intravenous administration of drugs to rat spinal cord neurones in vivo and bath application to rat cortical wedges in vitro to evaluate MK-801 and other phencyclidine (PCP) receptor ligands as N-methylaspartate (NMA) antagonists, paying particular regard to the possible use-dependent nature of their action. MK-801, 0.1-0.5 mg/kg, was a selective and long-lasting NMA antagonist. We were unable to demonstrate significant use-dependent onset of antagonism of NMA by any of the drugs in vivo. Recovery, however, for MK-801 was use-dependent. In vitro there was a gradation with MK-801 being very use-dependent, followed by (PCP), cyclazocine and ketamine, the last showing little or no use-dependence. Results of experiments modulating the in vitro environment suggest that a significant difference between the in vitro and in vivo systems was temperature. Raising the temperature of the wedge chamber from 23 to 33 degrees C reduced the use-dependence of MK-801, and lowering the temperature to 13 degrees C increased the use-dependence of PCP. The mechanism of action of PCP receptor ligands is discussed in the light of these results.

Topics: Animals; Aspartic Acid; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; In Vitro Techniques; Ketamine; N-Methylaspartate; Phencyclidine; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine; Spinal Cord; Substance-Related Disorders