Discriminative Stimulus Effects Of Drugs Research Articles

Characterization of a Nicotine Discriminative Stimulus in Rhesus Monkeys

In general, the discriminative stimulus effects of drugs are examined following s.c. or i.m. administration; this may not be predictive of the effects of drugs that are abused by other means. Nicotine is primarily inhaled in the form of cigarette smoke. Here, two drug discrimination assays were used to compare the effects of nicotine administered i.v. or s.c. in rhesus monkeys responding under an FR5 schedule of stimulus shock termination. In monkeys discriminating 1.78 mg/kg nicotine s.c. (n=5), the ED50 of nicotine was 0.41 mg/kg. In monkeys discriminating 0.032 mg/kg nicotine i.v. (n=4), the ED50 of nicotine was 0.0067 mg/kg. In 3 of these monkeys, a dose of 3.2 mg/kg nicotine s.c. was required to substitute for the i.v. discriminative stimulus; up to 5.6 mg/kg nicotine did not substitute in the fourth monkey. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine antagonized the discriminative stimulus effects of nicotine in both discriminations; 1 mg/kg mecamylamine produced rightward shifts of the nicotine dose‐effect function of 3.2‐fold in the s.c. discrimination and a minimum 15‐fold in the i.v. discrimination. A dose of 3.2 mg/kg of the β2 subtype‐selective nAChR antagonist dihydro‐β‐erythroidine (DHβE) did not significantly antagonize the discriminative stimulus effects of nicotine in the s.c. discrimination. However, when combined with the training dose (0.032 mg/kg) of nicotine in the i.v. discrimination, DHβE dose‐dependently decreased discriminative stimulus effects (ED50=0.17 mg/kg). These results indicate there is a critical difference in the involvement of the β2 subtype of nAChR between the two discriminations that cannot be explained by the difference in training dose. Supported by USPHS Grant DA25267.

Mu opioid mediated discriminative-stimulus effects of tramadol: an individual subjects analysis.

Drug discrimination procedures use dose-dependent generalization, substitution, and pretreatment with selective agonists and antagonists to evaluate receptor systems mediating interoceptive effects of drugs. Despite the extensive use of these techniques in the nonhuman animal literature, few studies have used human participants. Specifically, human studies have not routinely used antagonist administration as a pharmacological tool to elucidate the mechanisms mediating the discriminative stimulus effects of drugs. This study evaluated the discriminative-stimulus effects of tramadol, an atypical analgesic with monoamine and mu opioid activity. Three human participants first learned to discriminate 100 mg tramadol from placebo. A range of tramadol doses (25 to 150 mg) and hydromorphone (4 mg) with and without naltrexone pretreatment (50 mg) were then administered to participants after they acquired the discrimination. Tramadol produced dose-dependent increases in drug-appropriate responding and hydromorphone partially or fully substituted for tramadol in all participants. These effects were attenuated by naltrexone. Individual participant records indicated a relationship between mu opioid activity (i.e., miosis) and drug discrimination performance. Our findings indicate that mu opioid activity may mediate the discriminative-stimulus effects of tramadol in humans. The correspondence of generalization, substitution, and pretreatment findings with the animal literature supports the neuropharmacological specificity of the drug discrimination procedure.

Role of training dose in drug discrimination

Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and the rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED(50) values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (a) changes in profiles of generalization between partial and full agonists; (b) reduced specificity of some discriminations at small training doses; and (c) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating 'drug versus drug' or 'dose versus dose' contingencies enabled detection of more subtle differences than the simple 'drug versus no drug' approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that use either within-subject or between-subject designs for studying the discriminative stimulus effects of drugs.

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies

Evaluation of the discriminative stimulus effects of drugs is a useful procedure for identification of receptor mediation of in vivo drug effects. This assay can be enhanced when the stimulus effects of different doses of agonist are evaluated. In the present study, rats were trained to discriminate small or large doses of nicotine from saline, and interactions of these effects with nicotinic receptor antagonists and partial agonists were determined. The insurmountable nicotine antagonist mecamylamine blocked both the discriminative stimulus and response rate-reducing effects of nicotine but was less effective against the large dose of nicotine. The α4β2*-selective, competitive antagonist dihydro-β-erythrodine (DHβE) antagonized the discriminative stimulus effects of both doses but was less effective against the larger training dose of nicotine. Schild analyses of DHβE suggested that different nicotinic receptor populations may be mediating the stimulus effects of large and small doses of nicotine. This suggestion was supported by observations that the discriminative stimulus effects of the partial agonist cytisine were more like those of the large dose than of the small dose of nicotine and that cytisine antagonized the effects of only the small nicotine dose. Varenicline produced nicotine-like effects in both training dose groups but reduced the discriminative stimulus effects of intermediate doses of nicotine in the group trained to the small dose of nicotine. Overall, these results suggest that small doses of nicotine produce their stimulus effects via α4β2* nicotine receptors, whereas larger doses of nicotine recruit additional nicotine receptor subtypes, as revealed by drug discrimination assays in rats.

Pavlovian Extinction of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats Varies as a Function of Context

Operant extinction contingencies can undermine the discriminative stimulus effects of drugs. Here, nicotine (0.4 mg/kg) and ethanol (0.8 g/kg) first functioned as either an SD or SD, in SΔ, in a counterbalanced one-lever go/no-go (across sessions) operant drug discrimination procedure. Pavlovian extinction in the training context (levers removed) grossly undermined the response rates and discriminative stimulus functions of nicotine, but not ethanol; presentation of the drugs in the home cage had no impact on stimulus control for either drug but lowered overall response rates. This result was replicated between, and within, groups of rats that differed in the order of extinction phases. These data suggest that stimulus reinforcer relationships play a role in the discriminative stimulus effects of drugs with regard to response rate, but vary pharmacologically and as a function of the context in which extinction occurs.

Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ketanserin, and (R)-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907) in Rats

Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)(2A) receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT(2) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), 1.0 mg/kg 5-HT(2A) receptor antagonist ketanserin, or 0.1 mg/kg purported 5-HT(2A) receptor inverse agonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907). Discriminative control was established with each drug after 33 to 35 sessions. MDL100907 and ketanserin did not occasion DOM lever responding but attenuated the discriminative stimulus effects of DOM. DOM did not occasion responding on the drug-associated lever in rats discriminating MDL100907 or ketanserin, but attenuated the discriminative stimulus effects of both drugs. Ketanserin and ritanserin occasioned MDL100907-lever responding, whereas rats discriminating ketanserin responded only partially on the drug-associated lever after receiving MDL100907, ritanserin, or the alpha(1)-adrenergic antagonist prazosin. Combining prazosin with MDL100907 or ritanserin resulted in near-complete ketanserin-lever responding, indicating that the ketanserin stimulus involves both 5-HT(2A) and alpha(1)-adrenergic receptors. Administration of p-chlorophenylalanine methyl ester, then fenfluramine, significantly decreased cortical 5-HT, enhanced sensitivity to the discriminative stimulus effects of DOM, and occasioned partial MDL100907-lever responding. Collectively, these results show that DOM and MDL100907 discriminative stimulus effects are mediated by 5-HT(2A) receptors and that ketanserin discriminative stimulus effects involve both 5-HT(2A) and alpha(1)-adrenergic receptors. Results in 5-HT-depleted rats further suggest that the discriminative stimulus effects of MDL100907 might involve antagonism of endogenous 5-HT and/or inverse agonism at 5-HT(2A) receptors.

Discriminative stimulus properties of Δ 9-tetrahydrocannabinol (THC) in C57Bl/6J mice

Primarily, rats have served as subjects in Δ 9-tetrahydrocannabinol's (THC) discrimination studies although other species such as monkeys and pigeons have been used. While the introduction of the knockout and transgenic mice has vastly stimulated the study of the discriminative stimulus effects of drugs there is only a single published report of mice trained to discriminate THC. Thus, this study extended those results by providing a systematic replication that THC serves as an effective discriminative stimulus in mice and by further investigating the mechanisms of action involved in the THC discrimination model in the mouse. Male C57BL/6J mice were trained to discriminate 10 mg/kg THC from vehicle in 2-lever drug discrimination. THC fully and dose dependently substituted for itself. Cannabinoid indoles, except one with low cannabinoid CB 1 receptor affinity, substituted for THC. Anandamide failed to substitute for THC when administered alone but completely substituted when administered with the non-specific fatty acid amide hydrolase inhibitor, phenylmethylsulphonyl fluoride. As expected, nicotine failed to substitute for THC. Lastly, the cannabinoid CB 1 receptor antagonist rimonabant blocked THC's discriminative stimulus effects. Taken together these studies demonstrate THC's ability to produce discriminative stimulus effects as well as demonstrate its pharmacological specificity and mechanism of action in a two-lever drug discrimination mouse model.

Pavlovian-Instrumental Transfer of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats

To date, only 1 study has evaluated the impact of a Pavlovian drug conditional stimulus (CS) on operant responding. A within-subject operant 1-lever go/no-go (across sessions) design was used to evaluate the impact of Pavlovian contingencies on the discriminative stimulus effects of nicotine (0.4 mg/kg) and ethanol (800 mg/kg) in male Sprague Dawley rats. Drugs were administered 10 min before each acquisition and test session. One drug predicted sessions of food reinforcement and the other drug predicted sessions of non reinforcement; stimulus roles were counterbalanced. In Experiment 1 (n = 7), operant lever pressing was initially maintained on a VI-30 s schedule of food reinforcement. This phase was followed by 20 (CS+ vs. CS-) Pavlovian drug discrimination training sessions without the levers present. Two extinction tests revealed significantly more operant lever pressing under the CS+ drug conditions compared to the CS- drug conditions, suggesting evidence for Pavlovian-instrumental transfer. Operant training significantly strengthened stimulus control. In Experiment 2 (n = 7), the drugs functioned as operant drug discriminative stimuli first. Next, the predictive roles of the drug S D s and S Δ S were reversed under Pavlovian CS- and CS+ contingencies, respectively. The original stimulus control was significantly undermined but was not reversed. These studies suggest that Pavlovian drug-reinforcer contingencies embedded within the operant 3-term contingency may play a partial role in mediating the discriminative stimulus effects of drugs.

Spontaneous Recovery During, But not Following, Extinction of the Discriminative Stimulus Effects of Nicotine in Rats: Reinstatement of Stimulus Control

Extinction of the discriminative stimulus effects of drugs has received little research attention. Using a one-lever food-reinforcement (VI-1 min) operant procedure with rats (N = 16), the studies reported here assessed extinction, spontaneous recovery, and reinstatement of responding to the discriminative stimulus effects of nicotine. Experiment 1 found evidence for retention of differential responding to IP administrations of nicotine after a 3-month (87 days) delay following acquisition. Experiment 2 compared spontaneous recovery of discriminative control 2 and 4 weeks following extinction. Additionally, the impact of noncontingent reinforcement on discriminative control was evaluated (reinstatement). During extinction training, nicotine (.4 mg/kg) or saline was administered 15 min prior to each 15-min session, as they were during training, but responding was not reinforced under either stimulus condition. Spontaneous recovery (SR) of responding under the SD condition occurred during a session (11th) preceded by two consecutive SΔ sessions. Matched by response rate, 8 rats were randomly assigned to either a 2-week delay group or a 4-week delay group. There was no evidence for SR of discriminated responding to the drugs 2 or 4 weeks following the final extinction session. Between-group comparisons further revealed that SR did not vary as a function of delay following extinction. Reinstatement of stimulus control was observed following 2 brief sessions of noncontingent food delivery (levers retracted and conducted in the absence of the drug cues). These results suggest that the maintenance and extinction of the discriminative stimulus effects of nicotine are temporally stable. Theoretical ideas regarding drug self-administration, craving, and therapy are entertained.

Evaluation of the reinforcing and discriminative stimulus effects of 1,4-butanediol and γ-butyrolactone in rhesus monkeys

Metabolic precursors and prodrugs of γ-hydroxybutyrate (GHB), including 1,4-butanediol (BDL) and γ-butyrolactone (GBL), have sedative and anesthetic effects and might have positive reinforcing effects. BDL and GBL were evaluated using behavioral procedures that measure positive reinforcing effects and discriminative stimulus effects of drugs that modulate γ-aminobutyric acid (GABA) at the GABA A receptor complex. One group of rhesus monkeys could respond for saline or the barbiturate methohexital (i.v.) in a self-administration paradigm. Two other groups of monkeys discriminated the barbiturate pentobarbital (i.g.) or the benzodiazepine midazolam (s.c.) from saline in a drug discrimination paradigm; another group of monkeys was treated with the benzodiazepine diazepam (5.6 mg/kg/day, p.o.) and discriminated the benzodiazepine antagonist flumazenil (s.c.) from vehicle. In self-administration experiments, methohexital and not BDL (0.1–3.2 mg/kg/injection) or GBL (0.1–3.2 mg/kg/injection) reliably maintained responding above saline levels. BDL and GBL, up to doses that suppressed responding, did not substitute for pentobarbital, midazolam or flumazenil. The onset of action for both drugs to decrease response rate was delayed (90 min for GBL and 150 min for BDL). These results suggest that any abuse-related effects of BDL and GBL are qualitatively different from the abuse-related effects of GABA A receptor modulators and further indicate that BDL and GBL do not have positive reinforcing effects in rhesus monkeys experienced with self-administration of a short-acting sedative-hypnotic.

Four-choice drug discrimination in pigeons.

(+)Amphetamine was added as a training stimulus for pigeons previously trained to discriminate among pentobarbital, morphine and saline using a three-choice procedure. Pigeons quickly learned the four-choice drug discrimination. Generalization from the training drugs was similar to that established with simpler drug discriminations; pentobarbital generalized to chlordiazepoxide, morphine generalized to methadone, and (+)amphetamine generalized to cocaine and methamphetamine. Low doses of phencyclidine generalized to saline, while higher doses partially generalized to pentobarbital and (+)amphetamine. When dose-response curves were redetermined with a cumulative-dosing procedure, the same pattern of generalization occurred as under single-dose procedures. Dose-response curves were quantal under both the single-dose and the cumulative-dosing procedures. The four-choice procedure offers some important advantages for studying the discriminative stimulus effects of drugs that interact with multiple receptor subtypes and for studying drug mixtures.

Creation and First 20 Years of the Society for the Stimulus Properties of Drugs (SSPD)

Clinical observations and novels in the 19th century recognized that memory of some events can be retrieved only under the influence of the same drug condition that was present during the event. This dissociative effect of drugs probably reflects the same drug effects that were later called the discriminative stimulus effects of drugs. The Society for Stimulus Properties of Drugs (SSPD) was founded in 1978 as a forum for communications and periodic meetings on this drug effect. During its early years many of its members were psychologists, but subsequent to that time the most frequent research application has been for the pharmacological purpose of identifying new drugs that have the same discriminative stimulus attributes as a prototype training drug. The majority of members have been in the United States, but several major international meetings have been in Europe. The methods used by the society's members involve both neuropharmacological and psychological processes, allowing them to make unique contributions to the study of both mind and brain.

Discriminative Stimulus Effects of Drugs Acting at GABA A Receptors : Differential Profiles and Receptor Selectivity

The GABA A receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(ω) recognition sites, which form part of the GABA A receptor complex. Of particular interest are compounds with selectivity for the BZ 1(ω 1) receptor subtype including zolpidem, zaleplon, and Cl 218,872. BZ 1(ω 1)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(ω) receptor agonists are mediated by the BZ 1(ω 1) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ 2(ω 2) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.

Phencyclidine- and diazepam-like discriminative stimulus effects of inhalants in mice.

It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partial substitution. Fluorothyl and toluene produced no appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration-related partial substitution for PCP, whereas methoxyflurane, TCE, and fluorothyl did not substitute. The substitution of some these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D-aspartate antagonists as well as those of gamma amino butyric acid agonists.

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle.

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-D-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals.

Assessment of the MDA and MDMA Optical Isomers in a Stimulant-Hallucinogen Discrimination

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(+)-MDA 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.

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Punishment alters the discriminative stimulus effects of midazolam.

Experiment 1 examined the effects of punishment on the discriminative stimulus (DS) effects of midazolam (M) and pentobarbital (P) in 3 pigeons. Sessions began with a fixed-interval (FI) 3-min schedule of food reinforcement. After 40 min, either saline (S) or 0.56 mg/kg of M was injected. A drug-discrimination (DD) component began 10 min later. Pecking the left key produced grain after S injections, whereas pecking the right key produced grain after M. Dose-response curves for M and P were obtained under these conditions and also when every 30th peck during the FI was punished by shock. The introduction of punishment increased sensitivity to the DS effects of M and P. Experiment 2 examined whether a punishment history increases sensitivity to the DS effects of M. After DD training and testing, pecking was punished for 10 sessions. This history shifted the M dose-response curve to the left for 3 of 4 pigeons. These results emphasize the contribution of behavioral variables to the DS effects of drugs. Environmental variables appear to play a prominent role in guiding sensitivity to the subjective effects of drugs.

A bibliography of drug discrimination research, 1992???1994

The major content of this publication is a comprehensive bibliography of research into the discriminative stimulus effects of drugs in animal and human subjects for the period 1991-1994. The bibliography is accompanied by a detailed cross-index that facilitates access to this literature through keywords based on the drugs studied, how the drugs were used, and numerous other methodological variables such as species of subject and schedule of reinforcement. The article also explains how users may obtain access to the present and earlier versions of the database, which are available as computer disks and over the Internet. The easy access to this literature made possible by the database should increase the working efficiency of the many groups that employ drug discrimination methods and should also support dissemination of the knowledge acquired to a wider scientific community.