Interactions between N-methyl-D-aspartate receptor antagonists and the discriminative stimulus effects of morphine in rats

NMDA receptor antagonists have previously been reported to alter some pharmacological and behavioral effects of acute and chronic opioid administration. The present study assessed the interactions of NMDA antagonists with the discriminative stimulus properties of morphine. Adult male Long Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water under a two-lever fixed-ratio 10 schedule of food reinforcement. During test sessions. I.p. injections of the noncompetitive NMDA receptor antagonist dizocilpine (0.03-0.2 mg/kg), the competitive antagonists NPC 17742 (1-16 mg/kg), and SDZ 220-581 (0.1-3 mg/kg), the polyamine site antagonist eliprodil (3-17.3 mg/kg), the glycine-site partial agonist (+)-HA-966 (3-56 mg/kg), and the nonselective glutamate antagonist kynurenic acid (30-150 mg/kg) were coadministered with s.c. morphine (1-3.2 mg/kg; interaction tests) or water (generalization tests). In generalization tests, none of the compounds completely substituted for morphine. Concurrent administration of morphine and NMDA antagonists did not greatly alter the discriminative stimulus properties of morphine. Various doses of NPC 17742, SDZ 220-581, or (+)-HA-966 somewhat increased levels of morphine-appropriate lever selection, whereas some attenuation of morphine-lever selection was obtained when morphine was coadministered with eliprodil. These results show that NMDA antagonists have minimal interactions with the discriminative stimulus effects of morphine.     

Modulation of the discriminative stimulus and rate-altering effects of cocaine by competitive and noncompetitive N-methyl-D-aspartate antagonists

Preschool antecedents of the use of defense mechanisms were longitudinally studied using data from 90 nursery school children who were again evaluated at age 23. Defense use was determined by coding Thematic Apperception Test (H.A. Murray, 1943) stories with a method previously shown to be reliable and valid. The findings indicated continuity between preschool personality and subsequent defense use for male participants but little continuity for female participants. Young men's use of the age-inappropriate defense of denial was predicted by indications at ages 3-4 of low ego resiliency and psychological difficulties in the areas of emotion, intellect, impulse control, and social interactions.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine: however nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effect though a different mechanism that nicotine. Give bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.     

A three-choice discrimination procedure dissociates the discriminative stimulus effects of d-amphetamine and (±)-MDMA in rats.

(±)-3,4-Methylenedioxymethamphetamine (MDMA) produces subjective effects in humans that are similar to, but distinguishable from, those of psychostimulants. Drug discrimination studies in nonhumans have yielded inconsistent results regarding the similarities between MDMA and the psychomotor stimulant d-amphetamine. This study successfully used a 3-choice operant procedure to establish MDMA and d-amphetamine as discriminative stimuli in rats. Cocaine produced complete substitution for d-amphetamine, and LSD produced dose-dependent increases in MDMA-appropriate responding with nearly complete substitution (78%) for MDMA. The hallucinogen 2,5-dimethoxy-4-bromoamphetamine only partially substituted for MDMA and severely disrupted response rate. Fenfluramine, 3,4-methylenedioxyamphetamine-hydrochloride([+]-MDA), and (-)-MDA all produced complete substitution for MDMA. The serotonin-receptor antagonist pirenpirone only partially blocked MDMA discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin 1A receptor involvement in the discriminative stimulus effect of benzodiazepines in rats.

The purpose of this study was to examine the role of serotonin 1A (5-HT1A) receptors in the discriminative stimulus effects of benzodiazepines (BZs). Rats (Rattus norvegicus) were trained to discriminate either 7 mg/kg of chlordiazepoxide (CDP) or bretazenil from water. During substitution tests, CDP, bretazenil, and a novel β-carboline anxiolytic, abecarnil, produced > 95% responding on the drug-appropriate lever in both groups. In contrast, the selective 5-HT1A agonist (+)8-hydroxy-(di-N-dipropyl-2-amino)tetralin (8-OH-DPAT) did not substitute for either training drug but it potentiated the discriminative stimulus effects of a low dose of bretazenil or CDP, which suggests that serotonin may be involved in the discriminative stimulus effects of these compounds. Interestingly, 8-OH-DPAT did not potentiate the effects of a low dose of abecarnil in either group, nor did it potentiate the effects of a low dose of bretazenil in CDP-trained rats or a low dose of CDP in bretazenil-trained rats. The lack of reciprocity with abecarnil, CDP, and bretazenil may be due to the fact that only a single dose of each of these drugs was tested in combination with 8-OH-DPAT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The discriminative stimulus effects of clomethiazole in the rat

Rats were trained in a two-lever drug discrimination procedure using saline or clomethiazole (8 mg/kg, s.c. 15 min) as the training stimuli. A criterion of 9/10 days correct lever choice was adopted to select rats for substitution tests. The clomethiazole (CMZ) cue was not especially strong, and stable performance at this level was not achieved consistently. Nevertheless, in a series of substitution tests carried out in extinction, diazepam (3 mg/kg), chlordiazepoxide (10 mg/kg), phenobarbital (60 mg/kg), dizocilpine (0.1 mg/kg) and mianserin (3.0 mg/kg) were found to substitute for the training dose of CMZ. The first two of these produced a percentage choice of the drug lever equal to that produced by the training dose of CMZ (full generalization) whereas the latter three produced only partial generalization. Ethanol, muscimol, allopregnanolone, chlorpromazine and amitriptyline did not generalize to CMZ. CMZ is known to potentiate gamma-aminobutyric acid (GABAA) receptor function, a finding supported by the generalization to CMZ of the two benzodiazepines and phenobarbital. However, not all drugs acting at GABAA receptors generalized to CMZ. Although CMZ has no affinity for the N-methyl-D-aspartate (NMDA) receptor, it antagonizes a number of pharmacological responses mediated by NMDA receptors. The generalization in the drug discrimination procedure reported here support the suggestion that altering GABA activity can modulate NMDA-mediated responses. The lack of generalization after treatment with ethanol, chlorpromazine and amitriptyline suggests that the interoceptive cues are not mediated by a generalized sedation or drug-induced motor impairment.     

Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine

Two experiments were designed to study ultrastructural changes in porcine alveolar macrophages (PAM) inoculated with porcine reproductive and respiratory syndrome (PRRS) virus (experiment 1) and with PRRS virus and Haemophilus parasuis (experiment 2). In both experiments, the viral infectious dose represented a "multiplicity of infection" of 1. Viral infection alone induced minimal ultrastructural changes at this dose, consisting only of an increase in lysosome numbers. Mixed viral and bacterial infection induced the production of greatly increased numbers of phagosomes and phagolysosomes. The PAM were of low efficacy in phagocytizing H. parasuis. PRRS virus infection had only a minimal effect on the phagocytosis of H. parasuis by PAM. It is suggested that the virus induces PAM activation rather than PAM destruction.     

Dopamine D1/D2 antagonist combinations as antagonists of the discriminative stimulus effects of cocaine

Platelet-derived growth factor (PDGF) exists as a dimer composed of two homologous but distinct peptides termed PDGF-A and -B chains, and may exist as AA, AB, and BB isoforms. The PDGF-B chain has been implicated as a mediator of renal vascular rejection by virtue of up-regulated expression of its receptor, PDGF beta-receptor, in affected arteries. A role for PDGF-A chain in mediating intimal proliferation has been suggested in human atherosclerosis (Rekhter MD, Gordon D: Does platelet-derived growth factor-A chain stimulate proliferation of arterial mesenchymal cells in human atherosclerotic plaques? Circ Res 1994, 75:410), but no studies of this molecule in human renal allograft injury have been reported to date. We used two polyclonal antisera to detect expression of PDGF-A chain and one monoclonal antibody to detect PDGF-B chain by immunohistochemistry in fixed, paraffin-embedded tissue from 1) normal adult kidneys, 2) a series of renal transplant biopsies chosen to emphasize features of vascular rejection, and 3) allograft nephrectomies. Immunohistochemistry was correlated with in situ hybridization on adjacent, formalin fixed tissue sections from nephrectomies utilizing riboprobes made from PDGF-A and -B chain cDNA. PDGF-A chain is widely expressed by medial smooth muscle cells of normal and rejecting renal arterial vessels of all sizes by immunohistochemistry and in situ hybridization. PDGF-A chain is also expressed by a population of smooth muscle cells (shown by double immunolabeling with an antibody to alpha-smooth muscle actin) comprising the intima in chronic vascular rejection. In arteries demonstrating acute rejection, up-regulated expression of PDGF-A chain by endothelial cells was detected by both immunohistochemistry and in situ hybridization. In contrast, PDGF-B chain was identified principally in infiltrating monocytes within the rejecting arteries, similar to its localization in infiltrating monocytes in human atherosclerosis. Although less prominent than the case for PDGF-A chain, PDGF-B chain also was present in medial and intimal smooth muscle cells in both rejecting and nonrejecting renal arteries. PDGF-A and -B chains have now been localized at both the mRNA and protein levels to the intimal proliferative lesions of vascular rejection. These peptides, which are known stimuli for smooth muscle cell migration and proliferation in experimental vascular injury, may have similar stimulatory effects on smooth muscle cells in an autocrine and/or paracrine manner to promote further intimal expansion and lesion progression in this form of human vasculopathy.     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.

The study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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 (Fl) 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 Fl 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies on the neuronal circuits involved in the discriminative stimulus effects of 5-hydroxytryptamine1A receptor agonists in the rat

Rats were trained to discriminate 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, 1.25 mg/kg i.p.), a selective and nonselective 5-hydroxytryptamine1A (5-HT, serotonin) receptor agonist, respectively, from saline in a two-lever procedure. The selective 5-HT1A receptor agonist ipsapirone substituted completely for 8-OH-DPAT (ED50, 1.52 mg/kg) and 5-OMe-DMT substituted partially for 8-OH-DPAT, whereas 8-OH-DPAT (ED50, 0.07 mg/kg) and ipsapirone (ED50, 4.15 mg/kg) substituted completely for 5-OMe-DMT. These results suggest that the discriminative stimulus properties of both 8-OH-DPAT and 5-OMe-DMT are 5-HT1A receptor mediated, although 5-OMe-DMT may involve an additional interaction with other 5-HT receptor subtypes. 5-OMe-DMT substituted for 8-OH-DPAT after application in the lateral ventricle (ED50, 3.0 micrograms/rat) and the dorsal raphe nucleus (DRN, 1.1 micrograms/rat). After application in the DRN (ED50 range, 1.4-5.0 micrograms/rat) and the median raphe nucleus (2.3 micrograms/rat), and after bilateral application into the CA-4 region of the dorsal hippocampus (4.1 micrograms/rat), 8-OH-DPAT also produced responding on the 8-OH-DPAT lever. Ipsapirone also substituted for 8-OH-DPAT after application into the DRN and the hippocampus (ED50S, 38 and 62 micrograms/rat, respectively). The 5-HT1A mixed agonist-antagonist (1-(2-methoxyphenyl) 4-[4-(2-pthalimido)butyl]piperazine, i.p. NAN-190) attenuated the discriminative stimulus effects of 8-OH-DPAT injected i.p. (0.1 mg/kg), into the DRN (10 micrograms) or into the hippocampus (2 x 10 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Using behavior to elucidate receptor mechanisms: A review of the discriminative stimulus effects of benzodiazepines.

Drug discrimination procedures have been used to study receptor mechanisms of benzodiazepine (BZ) agonists with the goal of developing new therapeutic agents that retain positive effects of conventional BZ ligands yet have reduced side effects. The present review provides a synthesis of existing literature on discriminative stimulus effects of BZ agonists in order to elucidate their underlying receptor mechanisms, specifically in terms of intrinsic efficacy and receptor selectivity. The available evidence suggests that receptor selectivity is a critical determinant of the discriminative stimulus effects of BZ agonists. In particular, BZ-1 receptors appear to play a fundamental role, whereas the role of BZ-2 receptors remains elusive. In addition, data from many drug discrimination studies suggest that the conventional BZ agonist chlordiazepoxide may have reduced intrinsic efficacy compared with other BZ agonists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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. Flurothyl 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 flurothyl did not substitute. The substitution of some of 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The discriminative stimulus and its reputation: Role in the instigation of drug abuse.

The conditions that permitted the oral self-administration of a drug solution to develop as a reinforcing event for rats, so that a drug solution was preferred to a concurrently available vehicle (water), were elucidated. The genesis of a preference for a solution depended importantly on a history wherein the discriminative stimulus (a light SD) present in proximity to the drug-solution location had been associated with the self-administration of an ethanol solution. Once the SD was established, it stably determined fluid choice even if that fluid was a 2nd source of water. Results indicate that the sources of persistence and malleability of drug abuse behavior may lie in the instigating properties of established discriminative stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of gamma-aminobutyric acid agonists and N-methyl-D-aspartate antagonists on a multiple schedule of ethanol and saccharin self-administration in rats

Recently, it has been shown at both the cellular and behavioral levels that ethanol has effects on the N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)a receptor systems, leading to the possibility that the reinforcing effects of ethanol may be, at least partially, mediated via these receptor ionophores. In this study, a multiple schedule of ethanol and saccharin self-administration was used to study that possibility. Adult male Long-Evans rats were trained during 1-hr sessions to press on two different levers for 10% (w/v) ethanol and 0.1% (w/v) saccharin solutions, under an alternating 5-min, fixed-ratio-4 schedule of liquid availability. After training, tests were conducted with ethanol, NMDA antagonists and GABA agonists given before six consecutive sessions. Pretreatment with ethanol selectively decreased ethanol self-administration without altering saccharin self-administration. The competitive NMDA antagonist CPPene (D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid [SDZ EAA 494]) and the noncompetitive NMDA antagonist phencyclidine decreased both ethanol and saccharin self-administration. The GABA agonists pentobarbital and diazepam also failed to reduce ethanol self-administration, relative to saccharin. Although these results do not support the hypothesis that antagonism of the NMDA receptor system or activation of the GABA receptor system can selectively modify ethanol-reinforced responding, they identify important issues for designing the best strategies to be used to assess selective drug effects on ethanol self-administration.     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.