The Experts below are selected from a list of 10911 Experts worldwide ranked by ideXlab platform
Jack Bergman - One of the best experts on this subject based on the ideXlab platform.
-
cannabinoid antagonist Drug Discrimination in nonhuman primates
Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Brian D Kangas, Alexandros Makriyannis, Ani S Zakarian, Kiran Vemuri, Shakiru O Alapafuja, Shan Jiang, Spyros P Nikas, Jack BergmanAbstract:Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high-intake chronic users, there are no Food and Drug Administration (FDA)-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective in studying withdrawal from Drugs in several pharmacological classes is antagonist Drug Discrimination. The present studies were designed to examine this paradigm in squirrel monkeys treated daily with the long-acting CB1 agonist AM2389 (0.01 mg/kg) and trained to discriminate the CB1 inverse agonist/antagonist rimonabant (0.3 mg/kg) from saline. The discriminative-stimulus effects of rimonabant were both dose and time dependent and, importantly, could be reproduced by discontinuation of agonist treatment. Antagonist substitution tests with the CB1 neutral antagonists AM4113 (0.03-0.3 mg/kg), AM6527 (0.03-1.0 mg/kg), and AM6545 (0.03-1.0 mg/kg) confirmed that the rimonabant discriminative stimulus also could be reproduced by CB1 antagonists lacking inverse agonist action. Agonist substitution tests with the phytocannabinoid ∆9-tetrahydrocannabinol (0.1-1.0 mg/kg), synthetic CB1 agonists nabilone (0.01-0.1 mg/kg), AM4054 (0.01-0.03 mg/kg), K2/Spice compound JWH-018 (0.03-0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3-5.6 mg/kg), URB597 (3.0-5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0-10.0 mg/kg) revealed that only agonists with CB1 affinity were able to reduce the rimonabant-like discriminative stimulus effects of withholding daily agonist treatment. Although the present studies did not document physiologic disturbances associated with withdrawal, the results are consistent with the view that the cannabinoid antagonist Drug Discrimination paradigm provides a useful screening procedure for examining the ability of candidate medications to attenuate the interoceptive stimuli provoked by cannabis discontinuation. SIGNIFICANCE STATEMENT: Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high-intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist Drug Discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence.
-
Drug Discrimination in epibatidine trained monkeys agonists and antagonists effects of nicotinic Drugs
The FASEB Journal, 2015Co-Authors: Rajeev I. Desai, Michelle R Doyle, Jack BergmanAbstract:The behavioral effects of nicotinic agonists and antagonists were studied in squirrel monkeys using a two-lever Drug Discrimination procedure. Monkeys (n=4) were trained to discriminate i.m. injections of 0.001 mg/kg (+)-epibatidine (EPI)–a α4β2 selective nicotinic agonist that is pharmacologically similar and structurally distinct from nicotine (NIC)–from saline on a 10-response fixed-ratio schedule of stimulus-termination. Results show that high efficacy nicotinic agonists [(+)-EPI, (-)-EPI, NIC] substituted fully for (+)-EPI, whereas the highest doses of other nicotinic agonists produced intermediate levels of (+)-EPI-like discriminative-stimulus (SD) effects [varenicline (VAR), cytisine (CYT)] or did not substitute for (+)-EPI (lobeline). Minor tobacco alkaloids produced full (nornicotine, anabasine, myosmine, anatabine), intermediate (anabaseine) or no (cotinine) (+)-EPI-like effects. Pretreatment studies with nicotinic antagonists show that: a) mecamylamine (non-selective) unsurmountably antagonized...
-
evaluation of faah and mgl inhibition in cannabinoid Drug Discrimination
The FASEB Journal, 2015Co-Authors: Michael Z Leonard, Alexandros Makriyannis, Brian D Kangas, Shakiru O Alapafuja, Spyros P Nikas, Vidyanand G Shukla, Jack BergmanAbstract:The discriminative-stimulus (SD) effects of CB1 ligands can be reproduced in mice by non-selective inhibition of the anandamide-(AEA-) and 2-arachidinoyl glycerol-(2-AG-) inactivating enzymes, resp...
-
Drug Discrimination in methamphetamine trained rats effects of cholinergic nicotinic compounds
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Rajeev I. Desai, Jack BergmanAbstract:Accumulating evidence suggests that acetylcholine nicotinic systems may contribute importantly to the abuse-related effects of d-methamphetamine (d-MA). The present study was conducted to compare the effects of indirect dopamine (DA) agonists (d-amphetamine, d-MA, and l-methamphetamine), full [(−)-nicotine, anabaseine, (+)-epibatidine, (−)-epibatidine, isoarecolone] and partial (varenicline) nicotinic agonists, and other cholinergic compounds (mecamylamine, dihydro-β-erythroidine hydrobromide, methyllycaconitine, atropine, scopolamine, rivastigmine, and donepezil) in rats trained to discriminate 0.3 mg/kg i.p. d-MA from saline. All indirect DA agonists fully substituted for d-MA in a dose-related manner. Among nicotinic agonists, only (−)-nicotine fully substituted for d-MA in a dose-dependent manner, whereas all other nicotinic agonists and, to a limited extent, muscarinic antagonists produced partial d-MA-like responding. Other cholinergic compounds failed to produce d-MA-like discriminative stimulus effects. In Drug interaction studies, varenicline served to dose-dependently attenuate the d-MA-like effects of (−)-nicotine, whereas mecamylamine, but not varenicline, reduced the discriminative stimulus effects of the training dose of d-MA. Differences between (−)-nicotine and other nicotinic agonists may be related to their ability to activate the DA system. These results provide further evidence that nicotinic mechanisms may be useful neurochemical targets for the development of therapeutics for the management of monoaminergic stimulant abuse and addiction.
-
Drug Discrimination in methamphetamine trained monkeys effects of monoamine transporter inhibitors
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Paul W Czoty, Alexandros Makriyannis, Chinnasamy Ramaraj Ramanathan, Nicole H Mutschler, Jack BergmanAbstract:The involvement of brain monoamine systems in the discriminative stimulus effects of methamphetamine (MA) was studied in squirrel monkeys by evaluating the effects of differentially selective monoamine uptake inhibitors alone and in combination. In monkeys discriminating i.m. injections of 0.3 mg/kg MA from saline, methamphetamine (0.01-0.3 mg/kg), and dopamine transporter (DAT) inhibitors, including 1-{2-(bis(4-fluorophenyl)-methoxy)ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909; 1.0-17.8 mg/kg) and its analogs AM2502 (1.0-17.8 mg/kg), AM2506 (1.0-30.0 mg/kg), AM2515 (1.0-17.8 mg/kg), and AM2517 (1.0-5.6 mg/kg), produced dose-related increases in responding on the MA-associated lever and, at the highest doses, full substitution. The time course of MA-like effects was similar for equivalent (3.0 mg/kg) doses of GBR 12909 and its most potent analog, AM2517. Unlike the DAT blockers, the selective 5-hydroxytryptamine (serotonin) uptake inhibitor clomipramine (1.0-10.0 mg/kg) and the selective norepinepherine (NE) uptake inhibitor desipramine (1.0-10 mg/kg) produced responding primarily on the saline lever. The selective NE uptake inhibitor nisoxetine partially substituted at the highest dose tested (10.0 mg/kg). Pretreatment with GBR 12909 or AM2517 enhanced the discriminative stimulus effects of MA, shifting the dose-effect curve leftward. The NE uptake inhibitors desipramine or nisoxetine also enhanced the discriminative stimulus effects of MA, whereas clomipramine only attenuated them. These results support the view that dopaminergic mechanisms play a prominent role in the discriminative stimulus effects of MA in monkeys, whereas involvement of serotonergic and noradrenergic systems may be limited to a modulatory role.
Rick A. Bevins - One of the best experts on this subject based on the ideXlab platform.
-
pavlovian Drug Discrimination with bupropion as a feature positive occasion setter substitution by methamphetamine and nicotine but not cocaine
Addiction Biology, 2009Co-Authors: Jamie L. Wilkinson, Rick A. BevinsAbstract:Bupropion can serve as a discriminative stimulus (S(D)) in an operant Drug Discrimination task, and a variety of stimulants substitute for the bupropion S(D). There are no reports, however, of bupropion functioning as a Pavlovian occasion setter (i.e. feature positive modulator). The present experiment seeks to fill this gap in the literature by training bupropion in rats as a feature positive modulator that disambiguates when a light will be paired with sucrose. Specifically, on bupropion (10 mg/kg intraperitoneal) sessions, offset of 15-second cue lights were followed by brief delivery of liquid sucrose; saline sessions were similar except no sucrose was available. Rats readily acquired the Discrimination with more conditioned responding to the light on bupropion sessions. Bupropion is approved for use as a smoking cessation aid, and more recently has drawn attention as a potential pharmacotherapy for cocaine and methamphetamine abuse. Accordingly, after Discrimination training, we tested the ability of cocaine (1-10 mg/kg), methamphetamine (0.1 to 1 mg/kg) and nicotine (0.00625 to 0.2 mg/kg) to substitute for the bupropion feature. Nicotine (0.05 mg/kg) and methamphetamine (0.3 mg/kg) substituted fully for bupropion; cocaine did not substitute. These results extend previous research on shared stimulus properties between bupropion and other stimulants to a Pavlovian occasion setting function. Further, this is the first report of nicotine and methamphetamine substitution for bupropion. The overlap in stimulus properties might explain the effectiveness of bupropion as a smoking cessation aid and highlight the possible utility of bupropion for treatment of stimulant use disorder.
-
pavlovian Drug Discrimination with bupropion as a feature positive occasion setter substitution by methamphetamine and nicotine but not cocaine
Addiction Biology, 2009Co-Authors: Jamie L. Wilkinson, Rick A. BevinsAbstract:Bupropion can serve as a discriminative stimulus (S D ) in an operant Drug Discrimination task, and a variety of stimulants substitute for the bupropion S D . There are no reports, however, of bupropion functioning as a Pavlovian occasion setter (i.e., feature positive modulator). The present experiment seeks to fill this gap in the literature by training bupropion in rats as a feature positive modulator that disambiguates when a light will be paired with sucrose. Specifically, on bupropion (10 mg/kg IP) sessions, offset of 15-sec cue lights were followed by brief delivery of liquid sucrose; saline sessions were similar except no sucrose was available. Rats readily acquired the Discrimination with more conditioned responding to the light on bupropion sessions. Bupropion is approved for use as a smoking cessation aid, and more recently has drawn attention as a potential pharmacotherapy for cocaine and methamphetamine abuse. Accordingly, after Discrimination training we tested the ability of cocaine (1 to 10 mg/kg), methamphetamine (0.1 to 1 mg/kg), and nicotine (0.00625 to 0.2 mg/kg) to substitute for the bupropion feature. Nicotine (0.05 mg/kg) and methamphetamine (0.3 mg/kg) substituted fully for bupropion; cocaine did not substitute. These results extend previous research on shared stimulus properties between bupropion and other stimulants to a Pavlovian occasion setting function. Further, this is the first report of nicotine and methamphetamine substitution for bupropion. The overlap in stimulus properties might explain the effectiveness of bupropion as a smoking cessation aid and highlight the possible utility of bupropion for treatment of stimulant use disorder.
-
nornicotine partially substitutes for amphetamine in a Drug Discrimination paradigm in rats
Pharmacology Biochemistry and Behavior, 1997Co-Authors: M. T. Bardo, Peter A Crooks, Rick A. Bevins, Jennifer E. Klebaur, Linda P DwoskinAbstract:Abstract Rats were trained in a two-lever food-reinforced operant task to discriminate (+)-amphetamine (1 mg/kg) from saline. After Discrimination training stabilized, test doses of (+)-amphetamine (0.0625–2.0 mg/kg), (−)-nicotine (0.1–1.0 mg/kg), or (−)-nornicotine (1–10 mg/kg) were assessed for their ability to substitute for the (+)-amphetamine training dose during brief test sessions in which food reinforcement was withheld. As expected, as the test dose of (+)-amphetamine increased, there was a dose-related increase in Drug-appropriate responding, with both 1 and 2 mg/kg test doses substituting fully for the (+)-amphetamine training dose. Both (−)-nicotine and (−)-nornicotine showed partial substitution (approximately 50% Drug-appropriate responding) for the (+)-amphetamine training dose, with (−)-nicotine being more potent than (−)-nornicotine. Rate suppressant effects prevented the assessment of higher doses of (−)-nicotine or (−)-nornicotine. Thus, while (−)-nicotine and (−)-nornicotine share similar discriminative stimulus properties, the mechanism that mediates this effect appears to differ, at least in part, from that activated by (+)-amphetamine.
-
individual differences in response to novelty amphetamine induced activity and Drug Discrimination in rats
Behavioural Pharmacology, 1997Co-Authors: Rick A. Bevins, Jennifer E. Klebaur, Michael T BardoAbstract:Rats were pre-tested in several individual difference screens--novelty-induced activity, novelty-induced place preference, novel-object interaction, and amphetamine-induced activity. Rats that were more sensitive to the locomotor effects of amphetamine were more active in an inescapable novel environment and displayed a greater preference for a novel environment. All animals were then trained to discriminate amphetamine (1 mg/kg) from saline in a two-bar Discrimination procedure using food-maintained responding. After acquisition of the Discrimination (mean = 37 trials), two amphetamine generalization tests (0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg) were conducted. In the second generalization test, rats that were more sensitive to the activating effect of amphetamine were also more sensitive to the discriminative stimulus effects of amphetamine (i.e. lower median effective dose). Moreover, high responders in the novelty-induced activity and novelty-induced place preference screens were more sensitive than low responders to the bar-press suppressant effects of amphetamine in the first generalization test. The relationships are discussed in terms of identifying processes common to the screens (e.g. stress and reward).
Lisa E Baker - One of the best experts on this subject based on the ideXlab platform.
-
re evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female sprague dawley rats
Behavioural Pharmacology, 2020Co-Authors: Keli A Herr, Lisa E BakerAbstract:Recent discoveries from clinical trials with psychedelic-assisted therapy have led to a resurgence of interest in the psychopharmacology of lysergic acid diethylamide (LSD). Preclinical Drug Discrimination is an invaluable tool to investigate the neurochemical mechanisms underlying subjective Drug effects. The current study extends previous Drug Discrimination research by including both sexes. Adult female (n = 8) and male (n = 8) Sprague-Dawley rats were trained to discriminate 0.08 mg/kg LSD from saline under a fixed ratio 20 schedule of food reinforcement. Substitution tests were conducted with several substances, including other serotonergic hallucinogens, psychostimulants, mixed psychedelic-stimulants and synthetic cathinones. Stimulus antagonist tests were conducted with selected serotonin and dopamine antagonists. LSD-substitution with serotonergic hallucinogens was comparable between sexes. Modest but intriguing differences were observed between male and female rats in the extent of partial substitution by 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine enantiomers and the synthetic cathinones, 3,4-methylenedioxypyrovalerone and 4-methylmethcathinone. Dopamine antagonists failed to block the LSD cue in both sexes and exerted stronger rate suppressant effects in male rats. The 5-hydroxytryptamine antagonist, (R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol (MDL 100 907) blocked LSD Discrimination in both sexes, although complete blockade was evident at lower doses in male rats. These results support previous findings regarding the prominent role of serotonergic activities underlying LSDs discriminative stimulus effects in male rats and generalize these findings to female rats. In consideration of the rising popularity in psychedelic-assisted psychotherapy, further research may be warranted to evaluate possible sex differences in the behavioral and subjective effects of LSD.
-
differential effects of 3 4 methylenedioxypyrovalerone mdpv and 4 methylmethcathinone mephedrone in rats trained to discriminate mdma or a d amphetamine mdma mixture
Psychopharmacology, 2016Co-Authors: Eric L Harvey, Lisa E BakerAbstract:Recent reports on the abuse of novel synthetic cathinone derivatives call attention to serious public health risks of these substances. In response to this concern, a growing body of preclinical research has characterized the psychopharmacology of these substances, particularly mephedrone (MEPH) or methylenedioxypyrovalerone (MDPV), noting their similarities to 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. Few studies have utilized Drug Discrimination methodology to characterize the psychopharmacological properties of these substances. The present study employed a rodent Drug Discrimination assay to further characterize the stimulus effects of MEPH and MDPV in comparison to MDMA and to a Drug mixture comprised of d-amphetamine and MDMA. Eight male Sprague-Dawley rats were trained to discriminate 1.5 mg/kg MDMA, and eight rats were trained to discriminate a mixture of 1.5 mg/kg MDMA and 0.5 mg/kg d-amphetamine (MDMA + AMPH) from vehicle. Substitution tests were conducted with MDMA, d-amphetamine, MDPV, MEPH, and cocaine. Dose-response curves generated with MDMA and MEPH were comparable between training groups. In contrast, AMPH, MDPV, and cocaine produced only partial substitution in animals trained to discriminate MDMA but produced full substitution in animals trained to discriminate the MDMA + AMPH mixture. These findings indicate that MDPV’s effects may be more similar to those of traditional psychostimulants, whereas MEPH exerts stimulus effects more similar to those of MDMA. Additional experiments with selective DA and 5-hydroxytryptamine (5-HT) receptor antagonists are required to further elucidate specific receptor mechanisms mediating the discriminative stimulus effects of MDPV and mephedrone.
-
discriminative stimulus properties of 1 25 and 5 0 mg kg doses of clozapine in rats examination of the role of dopamine serotonin and muscarinic receptor mechanisms
Pharmacology Biochemistry and Behavior, 2004Co-Authors: Adam J Prus, Lisa E Baker, Herbert Y MeltzerAbstract:Abstract Clozapine (CLZ), an atypical antipsychotic Drug (APD), produces minimal extrapyramidal side effects (EPS) and has significant advantages for treating both positive and negative symptoms in schizophrenic patients. CLZ has been established as a discriminative cue in the Drug Discrimination paradigm and in generalization tests the CLZ cue is more selective for atypical, rather than typical, APDs. However, greater selectivity for atypical antipsychotics has been demonstrated with a lower (1.25 mg/kg) CLZ training dose in rats [Psychopharmacology, 149 (2000) 189], rather than the traditional, higher training dose (5.0 mg/kg). It is therefore of interest to evaluate the properties mediating the 1.25 mg/kg CLZ discriminative cue. In the present study, rats were trained to discriminate either 1.25 mg/kg ( N =7) or 5.0 mg/kg ( N =7) CLZ from vehicle in a two-lever Drug Discrimination task. The typical antipsychotic haloperidol (0.1–0.4 mg/kg) did not substitute for either CLZ cue, whereas the atypical antipsychotic melperone (0.37–3.0 mg/kg) provided full substitution in both groups (>80% CLZ-appropriate responding). The 5-HT 1A receptor agonist (+)-8-OH-DPAT (0.04–0.16 mg/kg), and the selective 5-HT 2A receptor antagonist M100907 (0.03–1.0 mg/kg) did not produce substitution in either group. (+)-8-OH-DPAT combined with haloperidol (0.05 mg/kg) engendered only partial substitution (>60% CLZ-appropriate responding) for both CLZ cues, and M100907 combined with haloperidol (0.05 and 0.1 mg/kg doses) failed to provide substitution in either group. Trihexyphenidyl (0.18–6.0 mg/kg), a muscarinic M 1 -preferring receptor antagonist, engendered full substitution for the 1.25 mg/kg CLZ cue, but only partial substitution for the 5.0 mg/kg CLZ cue. These results provide evidence that antagonism at the muscarinic M 1 receptor is sufficient to provide 1.25 mg/kg CLZ-like discriminative stimulus effects.
-
serotonergic dopaminergic mediation of mdma s discriminative stimulus effects in a three choice Discrimination
Pharmacology Biochemistry and Behavior, 2003Co-Authors: Amy K Goodwin, Dori M Pynnonen, Lisa E BakerAbstract:Methylenedioxymethamphetamine (MDMA; ''Ecstasy'') is a common Drug of abuse that is often described as both a psychostimulant and a hallucinogen. Two-choice Drug Discriminations (i.e. Drug vs. nonDrug) in nonhumans comparing the discriminative stimulus properties of MDMA to psychostimulants or hallucinogens have produced somewhat inconsistent findings. The relative contribution of serotonergic versus dopaminergic actions to MDMA's discriminative stimulus effects may depend on the training stimulus conditions employed. We have previously demonstrated that rats can learn to discriminate the effects of MDMA and D-amphetamine in a three-choice Drug Discrimination procedure, and that LSD produced nearly complete substitution for MDMA under these conditions, and fenfluramine fully substituted for MDMA. In the present study, 12 rats were trained to discriminate LSD (0.08 mg/kg) and MDMA (1.5 mg/kg) from saline in a three-choice Drug Discrimination procedure under a fixed-ratio (FR) 10 schedule of food reinforcement. D-Amphetamine produced only partial substitution for MDMA while fenfluramine produced complete stimulus generalization. Low doses of D-amphetamine and fenfluramine produced greater stimulus generalization when administered in combination than when given alone. The serontonin2 antagonist MDL-100,907 only partially blocked the MDMA cue, but completely antagonized LSD Discrimination. The dopamine antagonist haloperidol also failed to block MDMA Discrimination. These results indicate that 5-HT release is a salient feature to MDMA's discriminative stimulus effects but that MDMA produces a compound discriminative stimulus. D 2003 Elsevier Science Inc. All rights reserved.
-
assessment of the mda and mdma optical isomers in a stimulant hallucinogen Discrimination
Pharmacology Biochemistry and Behavior, 1997Co-Authors: Lisa E Baker, M M TaylorAbstract:The phenylisopropylamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) have been compared to both psychostimulants and hallucinogens in Drug Discrimination investigations. The stereoisomers of these compounds, in particular those of MDA, appear to produce differential effects. Previous studies have demonstrated that animals trained to discriminate amphetamine from vehicle generalize to the S(+)-isomers but not the R(-)-isomers of MDA and MDMA while animals trained to discriminate LSD from saline generalize to R(-)-MDA and neither isomer of MDMA. However, animals trained to discriminate mescaline from vehicle generalize to both stereoisomers of these phenylisopropylamine derivatives. The present study consisted of two experiments in which a three-choice Drug Discrimination procedure was employed to compare the stereoisomers of MDA and MDMA to both amphetamine and either mescaline (experiment one) or LSD (experiment two). Sixteen male Sprague-Dawley rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and mescaline (12.5 mg/kg) and eight rats were trained to discriminate S(+)-amphetamine (1.0 mg/kg) and LSD (0.08 mg/kg) from saline in three-choice, food reinforced Drug Discrimination procedures. Substitution tests were administered with the isomers of MDA and MDMA. In the second experiment, substitution tests were also administered with lower doses of each training compound and with the stimulant cocaine and the hallucinogen 2,5-dimethoxy-4-methylphenylisopropylamine (DOM). In both experiments, all of the isomers produced very few responses on the S(+)-amphetamine lever. In the first experiment, R(-)-MDA and R(-)-MDMA produced nearly complete substitution for mescaline. The results of the second experiment revealed partial substitution for LSD with both isomers of MDMA and S(+)-MDA, and nearly complete substitution with R(-)MDA for LSD. The present findings do not support previous reports that S(+)-MDMA and S(+)-MDMA substitute for S(+)-amphetamine. The three-lever Drug Discrimination procedure may provide a more sensitive behavioral assay in which to examine the discriminative stimulus effects of Drugs with compound stimulus properties.
Anton Bespalov - One of the best experts on this subject based on the ideXlab platform.
-
Drug Discrimination analysis of nmda receptor channel blockers as nicotinic receptor antagonists in rats
Psychopharmacology, 2005Co-Authors: E S Zakharova, Wojciech Danysz, Anton BespalovAbstract:Rationale Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in Drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists.
-
Drug Discrimination analysis of nmda receptor channel blockers as nicotinic receptor antagonists in rats
Psychopharmacology, 2005Co-Authors: E S Zakharova, Wojciech Danysz, Anton BespalovAbstract:Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in Drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists. The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle. Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03–0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1–10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075–0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1–3 mg/kg, s.c.) and MRZ 2/621 (0.3–10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3–10 mg/kg, i.p.). In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED50=0.67 mg/kg) and MRZ 2/621 (ED50=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose–response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding. NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.
Joseph H Porter - One of the best experts on this subject based on the ideXlab platform.
-
Drug Discrimination historical origins important concepts and principles
Current topics in behavioral neurosciences, 2018Co-Authors: Joseph H Porter, Adam J Prus, Donald A OvertonAbstract:Research on the stimulus properties of Drugs began with studies on state dependent learning during the first half of the twentieth century. From that research, an entirely new approach evolved called Drug Discrimination. Animals (including humans) could discriminate the presence or absence of a Drug; once learned, the Drug could serve as a discriminative stimulus, signaling the availability or nonavailability of reinforcement. Early Drug Discrimination research involved the use of a T-maze task, which evolved in the 1970s into a two-lever operant Drug Discrimination task that is still used today. A number of important concepts and principles of Drug Discrimination are discussed. (1) The discriminative stimulus properties of Drugs are believed in large part to reflect the subjective effects of Drugs. While it has been impossible to directly measure subjective effects in nonhuman animals, Drug Discrimination studies in human subjects have generally supported the belief that discriminative stimulus properties of Drugs in nonhuman animals correlate highly with subjective effects of Drugs in humans. In addition to the ability of the Drug Discrimination procedure to measure the subjective effects of Drugs, it has a number of other strengths that help make it a valuable preclinical assay. (2) Drug Discrimination can be used for classification of Drugs based on shared discriminative stimulus properties. (3) The phenomena of tolerance and cross-tolerance can be studied with Drug Discrimination. (4) Discriminative stimulus properties of Drugs typically have been found to be stereospecific, if a Drug is comprised of enantiomers. (5) Discriminative stimulus properties of Drugs reflect specific CNS activity at neurotransmitter receptors. (6) Both human and nonhuman subjects display individual differences in their sensitivity to discriminative stimuli and Drugs. (7) The Drug Discrimination procedure has been used extensively as a preclinical assay in Drug development. This chapter is the first in the volume The Behavioural Neuroscience of Drug Discrimination, which includes chapters concerning the discriminative stimulus properties of various classes of psychoactive Drugs as well as sections on the applications and approaches for using this procedure.
-
the metabolites n desmethylclozapine and n desmethylolanzapine produce cross tolerance to the discriminative stimulus of the atypical antipsychotic clozapine in c57bl 6 mice
Behavioural Pharmacology, 2011Co-Authors: Jason M Wiebelhaus, Kevin A Webster, Herbert Y Meltzer, Joseph H PorterAbstract:It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the Drug Discrimination paradigm. This study examined the ability of N-desmethylclozapine and N-desmethylolanzapine (metabolites of the atypical antipsychotic Drugs cloza
-
serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in c57bl 6 mice
Psychopharmacology, 2005Co-Authors: Scott D Philibin, Adam J Prus, Alan L Pehrson, Joseph H PorterAbstract:Rationale The atypical antipsychotic Drug (APD) clozapine (CLZ) has been shown to have a robust discriminative cue in rats, pigeons, and monkeys in two-choice Drug Discrimination procedures.
