Drug Discrimination Studies Research Articles

Preclinical evaluation of abuse potential of the peripherally-restricted kappa opioid receptor agonist HSK21542

HSK21542 is a peripherally-restricted kappa opioid receptor (KOR) agonist developed for pain treatment. Because of the CNS pharmacological concern of opioid receptor activation, such as physical dependence and addiction potential, an assessment of abuse potential of HSK21542 was required prior to marketing approval. The preclinical abuse potential assessments for HSK21542 included the following studies: 1) intravenous self-administration study to explore the relative reinforcing efficacy in rats self-administering remifentanil; 2) rat drug discrimination study to examine the pharmacological similarity of the interoceptive or subjective effects of HSK21542 in rats discriminating pentazocine; 3) rat conditioned place preference (CPP) paradigm to test the rewarding effects; 4) rat natural physical dependence-spontaneous withdrawal study in rats chronically treated with HSK21542; 5) naloxone-precipitated withdrawal assay following chronic HSK21542 exposure to evaluate its physical dependence potential. The results showed that HSK21542 was devoid of behavioral evidence of positive reinforcing effect and did not share similar discriminative stimulus effects with pentazocine. HSK21542 also did not produce CPP in rats. In addition, HSK21542 did not produce spontaneous withdrawal or naloxone-precipitated withdrawal in rats with chronic treatments. Collectively, these preclinical findings suggest that HSK21542 has no abuse potential in animals, which demonstrate low abuse potential in humans.

S34 - Optimizing the Training Conditions of Rats in Nicotine Drug Discrimination Studies

S34 - Optimizing the Training Conditions of Rats in Nicotine Drug Discrimination Studies

The neuropharmacological properties of α-pyrrolidinobutiothiophenone, a new synthetic cathinone, in rodents; role of the dopaminergic system.

α-Pyrrolidinobutiothiophenone (α-PBT) is a chemical derivative of cathinone, a structural analogue of amphetamine. Until now, there have been a few previous neurochemical or neurobehavioural studies on the abuse potential of α-PBT. We examined the abuse potential of α-PBT by measuring psychomotor, rewarding, and reinforcing properties and methamphetamine-like discriminative stimulus effects in rodents using locomotor activity, conditioned place preference, self-administration, and drug discrimination studies. To clarify the underlying neuropharmacological mechanisms, we measured dopamine levels and neuronal activation in the dorsal striatum. In addition, we investigated the role of the dopamine D1 receptor or D2 receptors in α-PBT-induced hyperlocomotor activity, conditioned place preference, and the methamphetamine-like discriminative stimulus effect of α-PBT in rodents. α-PBT promoted hyperlocomotor activity in mice. α-PBT induced drug-paired place preference in mice and supported self-administration in rats. In a drug discrimination experiment, α-PBT fully substituted for the discriminative stimulus effects of methamphetamine in rats. Furthermore, α-PBT increased dopamine levels and c-Fos expression in the dorsal striatum of mice, which was associated with these behaviours. Finally, pretreatment with the D1 receptor antagonist SCH23390 or the D2 receptors antagonist eticlopride significantly attenuated acute or repeated α-PBT-induced hyperlocomotor activity, place preference, and the methamphetamine-like discriminative stimulus effects in rodents. These findings suggest that α-PBT has abuse potential at the highest dose tested via enhanced dopaminergic transmission in the dorsal striatum of rodents. The results provide scientific evidence for the legal restrictions of the recreational use of α-PBT.

A comparison of the reinforcing strength of cocaethylene and cocaine in monkeys responding under progressive-ratio and concurrent choice schedules of reinforcement

BackgroundIndividuals who use cocaine have high rates of co-morbid alcohol use and when ethanol and cocaine are administered concurrently, the metabolite cocaethylene is formed. Cocaethylene is equipotent to cocaine in blocking dopamine reuptake and substitutes for cocaine in drug discrimination studies. However, no previous work has directly compared the reinforcing strength of cocaine to cocaethylene. MethodsIn Experiment 1, three individually-housed adult male rhesus macaques self-administer cocaine under a progressive-ratio (PR) schedule of reinforcement, during daily 4-hr sessions. Under this schedule, the primary dependent variable is the number of injections received, or the break point (BP). Saline, cocaine (0.001–0.3mg/kg/injection) and cocaethylene (0.0003–0.1mg/kg/injection) dose-response curves were determined. In Experiment 2, two female cynomolgus and one rhesus macaque responded under a concurrent schedule of drug (cocaine or cocaethylene) vs. 1.0-g banana-flavored food pellets, during daily 1-hr sessions. ResultsBoth cocaine and cocaethylene functioned as reinforcers under the PR and concurrent choice schedules of reinforcement. Under the PR schedule, peak BPs were not significantly different, nor were ED50 values on the ascending limb, suggesting that cocaethylene has equal reinforcing strength and potency to cocaine. Under the concurrent drug-food choice procedure, cocaethylene was also equally potent to cocaine. ConclusionsUnder two schedules of reinforcement designed to assess reinforcing strength, cocaethylene and cocaine were equipotent and of equal reinforcing strength. Because cocaethylene has a longer duration of action, it is important for studies designed to evaluate treatments for cocaine use to also consider the effects of these interventions on cocaethylene.

Understanding the stimulus effects of nicotine and bupropion in a drug-drug discriminated goal-tracking task.

Bupropion is a non-nicotine medication for smoking cessation that has overlapping stimulus effects with nicotine as demonstrated in drug discrimination studies. Whether these shared stimulus effects will alter acquisition or maintenance of a discrimination between nicotine and bupropion is unknown. We sought to test this possibility using the drug discriminated goal-tracking (DGT) task and whether discrimination training history affected generalization and substitution tests. Sixty adult Sprague-Dawley rats (30M/30F) were equally split into three discrimination training groups: SAL-0.4NIC, 10BUP-0.4NIC, and 20BUP-0.4NIC. On nicotine days, all rats were administered subcutaneously 0.4mg/kg nicotine and had intermittent access to liquid sucrose. On intermixed non-reinforced days, rats were administered intraperitoneally saline, 10 or 20mg/kg bupropion. Upon completion, a range of nicotine and bupropion doses were assessed before substitution tests with varenicline and sazetidine-A were conducted. The SAL-0.4NIC and 10BUP-0.4NIC groups readily discriminated by session 8, as evidenced by increased dipper entries (goal-tracking) on nicotine days. The 20BUP-0.4NIC group was slower to acquire the discrimination. Female rats, regardless of group, had higher conditioned responding evoked by the lowest dose of nicotine (0.025mg/kg) in the dose-effect curve. The discrimination required rats to learn to withhold responding to the training dose of bupropion. This withholding of excitatory dipper entries generalized to other doses. Varenicline and sazetidine-A partially substituted for the nicotine stimulus, and this pattern did not differ with training history. We are the first to study a drug-drug discrimination using the DGT task. Females appeared to have a lower discrimination threshold for nicotine that was not impacted by the learning history. Further work on the importance of sex as a biological variable and how the complex interoceptive stimulus effects of nicotine can vary with training histories is needed.

Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans.

Characterization of 3,4-methylenedioxypyrovalerone discrimination in female Sprague-Dawley rats.

3,4-Methylenedioxypyrovalerone (MDPV), one of several synthetic cathinones, is a popular constituent of illicit 'bath salts'. In preclinical studies utilizing drug discrimination methods with male rodents, MDPV has been characterized as similar to both cocaine and 3,4-methylenedioxymethamphetamine-hydrochloride (MDMA). Whereas few drug discrimination studies have utilized female rats, the current study evaluated the discriminative stimulus effects of MDPV in 12 adult female Sprague-Dawley rats trained to discriminate 0.5 mg/kg MDPV from saline under a fixed ratio 20 schedule of food reinforcement. Stimulus substitution was assessed with MDPV and its enantiomers, other synthetic cathinones [alpha pyrrolidinopentiophenone-hydrochloride(α-PVP), 4-methylmethcathinone (4-MMC)], other dopamine agonists (cocaine, [+)-methamphetamine] and serotonin agonists [MDMA, lysergic acid diethylamide (LSD)] Stimulus antagonism was assessed with the dopamine D1 receptor antagonist, Sch 23390 and the D2 receptor antagonist, haloperidol. Cocaine and (+)-methamphetamine engendered full stimulus generalization to MDPV with minimal effects on response rate. LSD produced partial substitution, whereas MDMA and 4-MMC produced complete substitution, and all these serotonergic compounds produced dose-dependent response suppression. (S)-MDPV and α-PVP engendered full substitution with similar potency to the racemate, while (R)-MDPV failed to substitute up to 5 mg/kg. Both Sch 23390 and haloperidol attenuated the discrimination of low MDPV doses and essentially shifted the dose-response curve to the right but failed to block discrimination of the training dose. These findings are generally consistent with previous reports based exclusively on male rodents. Moreover, they confirm the contribution of dopaminergic mechanisms but do not rule out the possible contribution of other neurotransmitter actions to the interoceptive stimulus effects of MDPV.

Drug discrimination studies in rats: Impact of the route of administration

Drug discrimination studies in rats: Impact of the route of administration

Drug Discrimination: Historical Origins, Important Concepts, and Principles.

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.

Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs.

This chapter focuses on the translational value of drug discrimination as a preclinical assay for drug development. In particular, the importance of two factors, i.e., training dose and species, for drug discrimination studies with the atypical antipsychotic clozapine is examined. Serotonin receptors appear to be an important pharmacological mechanism mediating clozapine's discriminative cue in both rats and mice, although differences are clearly evident as antagonism of cholinergic muscarinic receptors is important in rats at a higher training dose (5.0mg/kg) of clozapine, but not at a lower training dose (1.25mg/kg). Antagonism of α1 adrenoceptors is a sufficient mechanism in C57BL/6 and 129S2 mice to mimic clozapine's cue, but not in DBA/2 and B6129S mice, and only produces partial substitution in low-dose clozapine discrimination in rats. Dopamine antagonism produces partial substitution for clozapine in DBA/2, 129S2, and B6129S mice, but not in C57BL/6 mice, and partial substitution is seen with D4 antagonism in low-dose clozapine drug discrimination in rats. Thus, it is evident that clozapine has a complex mixture of receptor contributions towards its discriminative cue based on the data from the four mouse strains that have been tested that is similar to the results from rat studies. A further examination of antipsychotic stimulus properties in humans, particularly in patients with schizophrenia, would go far in evaluating the translational value of the drug discrimination paradigm for antipsychotic drugs.

Discriminative Stimulus Properties of S(-)-Nicotine: "A Drug for All Seasons".

S(-)-Nicotine is the major pharmacologically active substance in tobacco and can function as an effective discriminative stimulus in both experimental animals and humans. In this model, subjects must detect and communicate the nicotine drug state versus the non-drug state. This review describes the usefulness of the procedure to study nicotine, presents a general overview of the model, and provides some relevant methodological details for the establishment of this drug as a stimulus. Once established, the (-)-nicotine stimulus can be characterized for dose response and time course effects. Moreover, tests can be conducted to determine the similarity of effects produced by test drugs to those produced by the training dose of nicotine. Such tests have shown that the stimulus effects of nicotine are stereoselective [S(-)-nicotine >R(+)-nicotine] and that other "natural" tobacco alkaloids and (-)-nicotine metabolites can produce (-)-nicotine-like effects, but these drugs are much less potent than (-)-nicotine. Stimulus antagonism tests with mecamylamine and DHβE (dihydro-β-erythroidine) indicate that the (-)-nicotine stimulus is mediated via α4β2 nicotinic acetylcholine receptors (nAChRs) in brain; dopamine systems also are likely involved. Individuals who try to cease their use of nicotine-based products are often unsuccessful. Bupropion (Zyban®) and varenicline (Chantix®) may be somewhat effective as anti-smoking medications because they probably produce stimulus effects that serve as suitable substitutes for (-)-nicotine in the individual who is motivated to quit smoking. Finally, it is proposed that future drug discrimination studies should apply the model to the issue of maintenance of abstinence from (-)-nicotine-based products.

Critical role for drug discrimination studies in the assessment of abuse liability of novel compounds

Critical role for drug discrimination studies in the assessment of abuse liability of novel compounds

Human drug discrimination: A primer and methodological review.

Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. (PsycINFO Database Record

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids

Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse.Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications.Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013).These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed.

Discriminative Stimulus Properties of Opioid Ligands: Progress and Future Directions.

Opioid receptors (MOP-r, KOP-r, DOP-r, as well as NOP-r) and their endogenous neuropeptide agonist systems are involved in diverse neurobiological and behavioral functions, in health and disease. These functions include pain and analgesia, addictions, and psychiatric diseases (e.g., depression-, anxiety-like, and stress-related disorders). Drug discrimination assays have been used to characterize the behavioral pharmacology of ligands with affinity at MOP-r, KOP-r, or DOP-r (and to a lesser extent NOP-r). Therefore, drug discrimination studies with opioid ligands have an important continuing role in translational investigations of diseases that are affected by these neurobiological targets and their pharmacotherapy.

The Discriminative Stimulus Properties of Drugs Used to Treat Depression and Anxiety.

Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

We know very little about the subjective effects of drugs in females.

Pharmaceutical companies assessing the nervous system effects of candidate therapeutics often use a behavioral assay in rodents that assesses the drug's subjective (internal stimulus) effects. Variants of this so-called "drug discrimination task" have also been widely used by basic scientist for more than 50 years to study the receptor actions of a host of ligands related to disease states and neuropathologies. Notably, most published research with this task has used male rats or mice. This situation is unfortunate and severely limits the utility of the research, given the well-documented differences between women and men on drug efficacy and safety, as well as known sex differences in the neural and behavioral effects of drugs. In this Viewpoint, we highlight the need for basic researchers, as well as pharmaceutical scientists, to include females in drug discrimination studies in a manner that allows detection and interpretation of potential sex differences.

Risky behaviors on the road: Do women and men act differently after drinking?

s / Drug and Alcohol Dependence 146 (2015) e34–e117 e105 Risky behaviors on the road: Do women and men act differently after drinking? Tanara R. Sousa1, Graciela Pasa1, Jeffrey Lunnen2, Flavio P. Pechansky1 1 Center for Drug and Alcohol Research, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 2 Johns Hopkins International Injury Research Unit, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States Aims: To compare differences between female andmale drivers regarding select risk factors in two Brazilian cities receiving intervention as part of the Global Road Safety Project. Methods: A knowledge, attitude and perception (KAP) survey was conducted among drivers in Palmas and Teresina. In October and November 2013, 1556 face to face interviews were conducted; samplingwasdonebyquotas, according todriver’s sex (70.9%male) and age. Results: The results show that females and males behave differently on the road. Females reported drinking and driving less (41.1% vs. 64.9% – p lofexidine (0.3mg/kg) = clonidine (0.3mg/kg) > guanfacine (1.8mg/kg). In drug discrimination studies, the discriminative stimulus effects of a cocaine-heroin mixture were not significantly altered by doses of brimonidine, guanfacine or clonidine below those that produced sedative effects and decreased operant responding to 50% decrease in the intake of cocaine/heroin mixtures without consistent modulation of their reinforcing strength. Conclusions: These data indicate that doses of alpha-2 agonists with behavioral side-effects that diminish over repeated treatment may be useful for in the management of polydrug (cocaine/heroin) addiction. Financial Support: (supported by DA 031299) http://dx.doi.org/10.1016/j.drugalcdep.2014.09.653 Differential effects of the benzodiazepines alprazolam and oxazepam on methamphetamine-related behaviors in rats Allyson Spence, Glenn F. Guerin, Nicholas E. Goeders Pharmacology, Toxicology, & Neuroscience, LSU Health Sciences Center, Shreveport, LA, United States Aims:Drugusers often combinebenzodiazepineswithpsychostimulants, such as methamphetamine (METH). Previous research has shown that not all benzo-diazepines have the same potential for abuse.While alprazolam (ALP) is highly preferred by drug users, oxazepam (OX) has a far lower abuse potential. We hypothesized thatMETHwould induce conditioned place preference (CPP), while OX and ALP would block the METH-induced CPP. We hypothesized that OX and ALP would attenuate METH discrimination. Methods: CPP was conducted to study the reward potential of the benzodiaz-epines OX and ALP when combined with METH to simulate polydrug abuse in rats (n=8/group). To determine if ALP and/orOXwouldalter the subjective effects ofMETH,wealso investigated the effects of these drugs on the discriminative stimulus effects of METH in rats (n=7/group). Rats were trained to discriminate METH (1.0mg/kg, ip) from saline using a two-lever operant, food-reinforced, drug discrimination design. The effects of ALP (2 and 4mg/kg, ip) and OX (5, 10, and 20mg/kg, ip) on METH discriminationwere determined by administering these drugs prior to variousdoses ofMETH (0, 0.125, 0.25, 0.5, 1, or 2mg/kg, ip) and then measuringwhether the rat pressed theMETHor saline-associated lever. Data were analyzed using one-way ANOVA. Results: METH produced a CPP, and OX blocked this METHinduced CPP. However, ALP did not block the METH-induced CPP. OX significantly attenuatedMETH discrimination in rats. However, we found that thehighdoseofALPaugmented the subjectiveeffects of lower doses of METH. Conclusions: The results of these experiments suggest that OX and ALP can differentially affect meth-related behaviors. OX attenuates the rewarding properties as well as the subjective effects of METH, while ALP may actually increase the rewarding properties of lower doses of METH. Future research will aim to identify the

Increasing food deprivation relative to baseline influences d-amphetamine dose–response gradients

Several studies using non-pharmacological discriminative stimuli have found that stimulus control, as evident in generalization gradients, changes when motivation for (i.e., deprivation of) the relevant reinforcer is altered. Drug-discrimination studies, however, have not consistently revealed such an effect. A procedural detail that may account for the lack of a reliable effect in drug-discrimination studies is that motivation was characteristically reduced relative to the training condition in these studies. The present experiment examined how substantially increasing motivation affects d-amphetamine discrimination. Rats initially were trained to discriminate d-amphetamine (1.0mg/kg) from vehicle (0mg/kg) injections under 22-h food deprivation conditions. Dose–response gradients were then obtained under 22-h and 46-h deprivation levels. The ED50 was significantly higher with greater deprivation. This finding suggests that increasing motivation relative to the training condition may reduce stimulus control by drugs, while decreasing it may sharpen stimulus control.