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Rationale: One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (S(D)) effects of each drug., Objectives: The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur., Methods: Male C57BL/6J mice were trained to discriminate ethanol (1.5 g/kg) alone or ethanol plus nicotine (0.4, 0.8, or 1.2 mg/kg base) in experiment 1 and nicotine (0.8 mg/kg) alone or nicotine plus ethanol (0.5, 1.0, or 2.0 g/kg) in experiment 2. Stimulus generalizations of the training mixtures to ethanol, nicotine, and the drug combination were assessed., Results: Ethanol (1.5 g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine S(D) was overshadowed by ethanol training doses > 0.5 g/kg in experiment 2, nicotine did potentiate the effects of low-dose ethanol., Conclusions: These findings are suggestive of dual mechanisms whereby ethanol (>0.5 g/kg) overshadows the S(D) effects of nicotine, and at lower doses (<1 g/kg) the salience of ethanol's S(D) effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.

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.

The gamma-aminobutyric acid (GABA)(A) receptors mediating the discriminative stimulus effects of ethanol were studied by comparing the potency of ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazol(1,5-a)benzodiazepine-3-carboxylate (Ro15-4513) and ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol(1,5-a)-benzodiazepine-3-carboxylate (flumazenil, Ro15-1788) to antagonize ethanol, pentobarbital (PB), and midazolam substitution for ethanol. Ro15-4513 has high affinity for receptors containing alpha(4/6) and alpha(5) subunits and lower affinity for alpha(1), alpha(2), and alpha(3) subunits. Flumazenil is nonselective for GABA(A) receptors containing alpha(1), alpha(2), alpha(3), and alpha(5) subunits and has low affinity for alpha(4/6)-containing receptors. Male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) were trained to discriminate ethanol (1.0 or 2.0 g/kg i.g., 30-min pretreatment) from water. Ethanol, PB, and midazolam dose-dependently substituted for ethanol (80% ethanol-appropriate responding). Ro15-4513 (0.003-0.56 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam dose-response functions rightward in a vast majority of monkeys tested (15/15, 16/17, and 11/12, respectively). In contrast, flumazenil (0.30-10.0 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam dose-response functions rightward in 9 of 16, 12 of 16, and 7 of 9 monkeys tested, respectively. In the monkeys showing antagonism with both Ro15-4513 and flumazenil, ethanol and PB substitution were antagonized more potently by Ro15-4513 than by flumazenil, whereas midazolam substitution was antagonized with similar potency. There were no sex or training dose differences, with the exception that flumazenil failed to antagonize ethanol substitution in males trained to discriminate 2.0 g/kg ethanol. GABA(A) receptors with high affinity for Ro15-4513 (i.e., containing alpha(4/6) and alpha(5) subunits) may be particularly important mediators of the multiple discriminative stimulus effects of ethanol through GABA(A) receptor systems.

Positive modulation of GABA(A) and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3alpha,5alpha-P), pregnanolone (3alpha,5beta-P), epiallopregnanolone (3beta,5alpha-P), and epipregnanolone (3beta,5beta-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3alpha,5beta-P HS)], and a structurally similar, adrenally derived steroid [3alpha-hydroxy-5-androstan-17-one (3alpha,5alpha-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3alpha-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3beta-hydroxysteroids and 3alpha,5beta-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3alpha,5beta-P and 3alpha,5alpha-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5beta-reduced isomer (3alpha,5beta-P), the 5alpha isomer of pregnanolone (3alpha,5alpha-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3alpha,5beta-P- and 3alpha,5alpha-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3alpha,5alpha-P.

Recent microdialysis studies showed that ethanol administration increases the release of taurine in various rat brain regions, and it was suggested that this increase in extracellular concentrations of taurine might mediate some of the neurochemical effects of ethanol. Previous drug discrimination studies showed that positive modulators of the GABA(A) receptor consistently substituted for ethanol discriminative stimulus effects. Since taurine is also believed to modulate GABA(A) receptor activity, this study addressed the hypothesis that taurine mediates the discriminative stimulus effects of ethanol due to GABA(A) activation. Male Long-Evans rats were trained to discriminate water from either 1 or 2 g/kg ethanol. In a first experiment, various taurine doses (0-500 mg/kg) were tested to investigate whether taurine substitutes for ethanol. In a second experiment, rats were pretreated with either 500 mg/kg taurine or an equivalent volume of saline before testing for ethanol discrimination with various ethanol doses (0-2.0 g/kg). The results showed that taurine does not substitute for ethanol at any tested doses. In addition, taurine pretreatments failed to modify the dose-response curve for ethanol discrimination. These results demonstrate that taurine is not directly involved in mediating the discriminative stimulus effects of ethanol. It is therefore very unlikely that the brain release of taurine observed after ethanol administration is implicated in the major pharmacological effects of ethanol, i.e. positive modulation of GABA(A) receptor, that mediate its discriminative stimulus effects.

Background: Genetically altered mice have been used to examine gene contributions to ethanol phenotypes. Recently, mice with a targeted deletion of the delta subunit of the gamma-aminobutyric acid (GABA)A receptor have been generated. These mice display decreased sensitivity to neuroactive steroids and altered responses to some behavioral effects of ethanol. Given the application of drug discrimination to characterize receptor-mediated stimulus effects of ethanol and given the data showing altered ethanol responses in mice lacking the delta subunit of the GABAA receptor, these mice were characterized in an ethanol-discrimination procedure. It has been shown that neurosteroids will substitute for the discriminative stimulus effects of ethanol, and this study aimed to determine whether the substitution patterns of neuroactive steroids or other GABAA-positive modulators would be altered in these mice., Methods: Twelve adult delta +/+ and delta-/- mice were trained to discriminate between ethanol 1.5 g/kg and saline in daily 15-min food-reinforced operant sessions. Once the discrimination was trained, substitution tests with ethanol, pentobarbital, midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK-801 were conducted., Results: Both delta+/+ and delta-/- mice acquired ethanol discrimination in a similar number of days. Ethanol, midazolam, alphaxalone, pregnanolone, and MK-801 fully substituted (>80%) for ethanol in both delta+/+ and delta-/- mice. Pentobarbital fully substituted for ethanol in delta-/- mice but only partially substituted (74%) for ethanol in delta+/+ mice. Androsterone, zolpidem, and morphine did not substitute for ethanol in either delta+/+ or delta-/- mice. There were no significant differences in the response rate-suppressing effects of any of the compounds between delta+/+ and delta-/- mice., Conclusions: The training dose of ethanol resulted in substitution of five GABAA receptor ligands, indicating a robust GABAA mediation of ethanol's discriminative stimulus effects. Deletion of the delta subunit of the GABAA receptor does not alter the acquisition of an ethanol/saline discrimination or the substitution patterns of GABAA-positive modulators. Therefore, the delta subunit is not necessary in the mediation of ethanol-like effects of any of the GABAA ligands tested, including sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid discriminative stimulus effects., (Copyright 2004 Research Society on Alcoholism)

Rationale: The current study was designed to extend our knowledge of the GABA(A) receptor system in mediating discriminative stimulus effects of ethanol in non-human primates., Objectives: To characterize the discriminative stimulus effects of ethanol, pentobarbital, midazolam, muscimol and morphine in male and female monkeys under different ethanol training conditions., Methods: Adult male (n=8) and female (n=10) Macaca fascicularis monkeys were divided into four groups and trained to discriminate 1.0 g/kg ethanol (n=8) versus water or 2.0 g/kg ethanol (n=10) versus water in a 2x2 design with training dose and sex as main group factors. Solutions were administered intragastrically (20% ethanol w/v) and responding was maintained under a fixed-ratio schedule of food reinforcement. Dose-response determinations of ethanol, pentobarbital, midazolam, muscimol and morphine were made under the training condition of 30 min pretreatment interval. The ethanol pretreatment interval in training sessions was then increased to 60 min and the effects of ethanol, pentobarbital and midazolam were redetermined., Results: Training dose influenced the ED50 of ethanol to produce substitution under both pretreatment intervals and pentobarbital to produce substitution under the 30-min pretreatment training interval. There were no group differences in sensitivity to midazolam. The potency of the ligands to produce ethanol substitution was consistent across groups with midazolam>pentobarbital>ethanol. There were no sex differences in substitution of the ligands for ethanol. Blood ethanol concentrations at the onset of ethanol training sessions were higher in the 2.0 g/kg groups and under longer pretreatment times, but were not different on the basis of sex., Conclusions: Pentobarbital and midazolam produce ethanol-like discriminative stimulus effects in male and female cynomolgus monkeys suggesting a significant GABA(A) component mediating the behavioral effects of ethanol. There was limited evidence that training dose of ethanol influenced substitution pattern of the GABA(A) ligands in cynomolgus monkeys, unlike previous findings in rats. Finally, there appear to be no sex differences in the profile of GABA(A) mechanisms involved in the discriminative stimulus effects of ethanol.

Ethanol's modulation of a number of receptor systems results in a heterogeneous discriminative stimulus complex. A previous study found that these heterogeneous discriminative stimulus effects were seemingly diminished when rats were trained to discriminate ethanol (2.0 g/kg) from pentobarbital (10.0 mg/kg). The present experiment was designed to extend these findings by using a lower training dose of ethanol (1.0 g/kg). Adult male Long-Evans rats (n = 7) discriminated pentobarbital (10.0 mg/kg; intragastric (i.g.)) from ethanol (1.0 g/kg; i.g.) from water (2.3 ml; i.g.) in a 3 lever, food-reinforced task. Substitution tests were conducted following intraperitoneal (i.p.) administration of GABA(A) positive modulators, noncompetitive NMDA antagonists, 5-HT1 agonists and isopropanol. The GABA(A) positive modulators diazepam, midazolam and allopregnanolone completely substituted for pentobarbital. Isopropanol completely substituted for ethanol, while the NMDA antagonists dizocilpine and phencyclidine partially substituted for ethanol. The 5-HT agonists RU 24969 and CGS 12066B did not result in complete substitution for ethanol or pentobarbital, although RU 24969 resulted in partial pentobarbital substitution. These data replicate and extend the previous findings that discriminating ethanol from pentobarbital attenuates the ethanol-like effects of GABA(A) positive modulators, NMDA antagonists and 5-HT1 agonists and results in a more specific ethanol cue. The outcome appears to be a conditional basis for the ethanol discrimination, where a full ethanol-like effect is produced only by drugs with pharmacological activity similar to the heterogenous effects of ethanol (e.g. other alcohols).

Neuroactive steroids exhibit rapid non-genomic central nervous system activity, including modulation of GABAA and NMDA receptors, two receptors known to mediate the effects of methanol. Neuroactive steroids that modulate GABAA receptors in a manner similar to ethanol were expected to potentiate the discriminative stimulus and/or rate-suppressing effects of ethanol. In contrast, neuroactive steroids that modulate GABAA or NMDA receptors in a manner opposite to ethanol were hypothesized to attenuate the effects of ethanol. Adult male rats were trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) from water (i.g.). Animals were pretreated with subthreshold doses (i.p.) of ethanol and neuroactive steroids and exposed to an acute stressor (n = 5), prior to conducting ethanol cumulative-dosing (i.p.) tests. Only ethanol and 3 beta, 5 beta-P pretreatments potentiated the discriminative stimulus effects of ethanol. None of the six neuroactive steroid manipulations attenuated the effects of ethanol. These results demonstrate that a neuroactive steroid, endogenous in humans, can enhance the interoceptive effects of ethanol.

A number of endogenous steroids exhibit rapid, nongenomic effects on the central nervous system and are called neuroactive steroids. The rapid mechanisms of action include modulation of gamma-aminobutyric acid type A (GABAA) and N-methyl-D-aspartate (NMDA) receptors, which are two receptors implicated in the behavioral effects of ethanol. It was hypothesized that neuroactive steroids that positively modulate GABAA receptors or negatively modulate NMDA receptors, analogous to the actions of ethanol, would produce discriminative stimulus effects similar to ethanol. Two groups of male Long-Evans rats (n = 6-8/group) were trained to discriminate between 1.0 or 2.0 g/kg ethanol (i.g.) and water (i.g.). The neuroactive steroids allopregnanolone, pregnanolone, epipregnanolone, allotetrahydrodeoxycorticosterone, pregnanolone sulfate, epipregnanolone sulfate, dehydroepiandrosterone, dehydroepiandrosterone sulfate, pregnenolone, and pregnenolone sulfate (PS), all administered i.p., were tested for substitution with acute and cumulative dosing procedures (n = 4-8/steroid). The GABAA-positive modulatory steroids allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone substituted for ethanol, as did the low-efficacy steroid 3beta,5beta-P. GABAA-negative modulators, such as dehydroepiandrosterone sulfate and PS, and all of the NMDA modulators tested, including PS, pregnanolone sulfate, and epipregnanolone sulfate, did not substitute for ethanol. These results show that certain endogenously occurring neuroactive steroids produce discriminative stimulus effects similar to those of ethanol.

The present study used a drug discrimination paradigm to characterize the contribution of separate receptor systems to the stimulus effects of different training doses of ethanol. In a two-lever drug discrimination paradigm two groups of adult male Long-Evans rats (n = 8 per group) were trained to discriminate either 1.0 g/kg ethanol from water or 2.0 g/kg ethanol from water, administered intragastrically (i.g.), 30 min prior to the start of daily sessions in which responding was maintained under a fixed ratio 20 schedule of food presentation. Following training, cumulative dosing substitution tests were conducted with the GABAA positive modulator pentobarbital (1-17 mg/kg, i.p.), the uncompetitive NMDA antagonist dizocilpine (0.01-0.3 mg/kg, i.p.) and the 5-HT1B/2C agonist m-trifluoromethylphenylpiperazine (TFMPP 0.17-1.7 mg/kg, i.p.). Next, the rats initially trained at 1.0 g/kg ethanol were retrained to discriminate 2.0 g/kg ethanol from water, and the rats initially trained at 1.0 g/kg were retrained to discriminate 2.0 g/kg ethanol from water. Both groups were then re-tested with the same ligands. Regardless of training history, animals currently discriminating 1.0 g/kg were more sensitive to the ethanol-like effects of TFMPP and pentobarbital compared to rats discriminating 2.0 g/kg ethanol. However, no difference in sensitivity to the ethanol-like effects of dizocilpine based on ethanol training dose was detected. These results support the view that ethanol is a heterogeneous discriminative stimulus comprised of GABAA, NMDA and 5-HT1B/2C receptor-mediated activity. Furthermore, changes in sensitivity to GABAA and 5-HT ligands as a function of training dose could be indicative of overshadowing by other components of ethanol's heterogeneous cue. Finally, it appears that the current profile of ethanol's heterogeneous stimulus effects, rather than an interaction with ethanol training history, determines the substitution pattern of specific receptor ligands.

Previous studies have suggested a modulatory role of the 5-HT2 receptor system in the behavioral effects of ethanol. The present study examined the discriminative stimulus effects of the 5-HT2A/2C agonist (-)-dimethoxy-4-indophenyl-2-aminopropane (DOI) and the 5-HT2A antagonist ketanserin in rats trained to discriminate either 1.5 g/kg of ethanol from water (intragastrically, n = 7) or 2.0 g/kg of ethanol from water (intragastrically, n = 8). In substitution tests, neither DOI (0.3 to 1.0 mg/kg, i.p.) nor ketanserin (3.0 to 17.0 mg/kg, i.p.) produced discriminative stimulus effects similar to either training dose of ethanol, although decreases in rates of responding were significant at the highest doses tested. Likewise, when given in combination with ethanol, neither 5-HT2 ligand shifted the ethanol-dose response determination in either the 1.5 or 2.0 g/kg ethanol training groups. DOI in combination with ethanol did not alter rates of responding, whereas ketanserin in combination with ethanol significantly decreased response rates. Thus, the 5-HT2A receptor ligands do not appreciably affect the discriminative stimulus effects of ethanol, in contrast to previous results with 5-HT1B ligands.

Previous drug discrimination studies have elucidated the importance of gamma-aminobutyric acidA (GABAA), N-methyl-D-aspartate (NMDA) glutamate, and serotonin (5-HT) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice operant drug discrimination procedure in an attempt to determine if salient GABAergic 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 pentobarbital (10.0 mg/kg; intragastrically (i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Stimulus substitution tests were conducted following the administration of allopregnanolone (1.0-17.0 mg/kg; intraperitoneally (i.p.)), diazepam (0.1-7.3 mg/kg; i.p.), midazolam (0.0056-17.0 mg/kg; i.p.), dizocilpine (0.01-0.56 mg/kg; i.p.), phencyclidine (1.0-5.6 mg/kg; i.p.), CGS 12066B (3-30 mg/kg; i.p.), RU 24969 (0.1-5.6 mg/kg; i.p.) and morphine (1 or 3.0 mg/kg; i.p.). Within the group, allopregnanolone and midazolam completely substituted (> 80%), and diazepam partly substituted (67%) for the discriminative stimulus effects of pentobarbital. Dizocilpine and phencyclidine partly substituted (58 and 57%, respectively) for ethanol without substantial pentobarbital-appropriate responding. RU 24969, CGS 12066B and morphine did not result in complete substitution for either ethanol or pentobarbital, although RU 24969 resulted in partial (68%) pentobarbital substitution. The ability to train the present three-choice discrimination in rats indicates that the discriminative stimulus effects of 10.0 mg/kg pentobarbital were separable from those of 2.0 g/kg ethanol. The results suggest that the pharmacological effects of ethanol, which can control behavior, may seemingly be modified by training conditions (two-versus three-choice discrimination procedures), to the extent that a receptor system prominently linked to the behavioral activity of ethanol (i.e. GABAA) appears no longer to be involved in the interoceptive effects of the drug.

N-methyl-D-aspartate (NMDA) antagonists substitute for the discriminative stimulus effects of ethanol, indicating that a component of ethanol's behavioral activity is produced via blockade of NMDA receptor/channel function. Recently, it has been reported that ethanol inhibits NMDA-stimulated nitric oxide synthase (NOS) activity in cortical neurons, thereby decreasing the formation of nitric oxide (NO) in the brain. These findings suggest that some of the behavioral effects of ethanol may be mediated by inactivation of NOS. The present study examined the role of NO formation in mediating the discriminative stimulus effects of ethanol. To address this hypothesis, an NOS inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) and an NMDA competitive antagonist, (D)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (CPPene), were administered to two groups of rats trained to discriminate 1.5 g/kg of ethanol (n = 6) or 2.0 g/kg (n = 7) of ethanol from water. After training, dose ranges of CPPene (3 to 17 mg/kg, ip) and L-NAME (100 to 780 mg/kg, ip) were tested for ethanol-like effects. L-NAME was also tested under a range of pretreatment times (20, 60, 90, and 120 min). An additional group of rats trained to discriminate 2.0 g/kg (n = 7) of ethanol from water was also tested with CPPene (10 mg/kg, ip) and L-NAME (100 and 300 mg/kg, ip) to verify data gathered from the original 2.0 g/kg of ethanol group tested with L-NAME after a 20-minute pretreatment. Although overall, 17 of 20 animals trained to discriminate ethanol from water exhibited complete substitution of CPPene for ethanol, L-NAME, without affecting response rates, did not consistently substitute for either 1.5 g/kg or 2.0 g/kg of ethanol. These results indicate that inhibition of NO formation is less effective than direct NMDA receptor antagonism in producing ethanol-like discriminative stimulus effects.

2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT), is a cocaine analog that inhibits dopamine uptake, binding with high affinity and selectivity to the dopamine transporter. In the present study, the behavioral effects of PTT were evaluated in two models of cocaine abuse: drug self-administration and drug discrimination. In the first experiment, rhesus monkeys (n = 3) were trained to self-administer cocaine (0.03 and 0.1 mg/kg/injection, i.v.) under a fixed-interval 5-min schedule. Presession administration of PTT (0.03-0.3 mg/kg, i.v.) or cocaine (0.3-3.0 mg/kg, i.v.) were evaluated. At both self-administered doses of cocaine, PTT decreased response rates and total session intakes and was approximately 0.5 to 1.0 log units more potent than cocaine. In experiment 2, the reinforcing effects of PTT (0.003-0.1 mg/kg/injection) were evaluated in a separate group of monkeys (n = 4) responding under a fixed-interval 5-min schedule of cocaine (0.03 mg/kg/injection) presentation. When substituted for cocaine, PTT maintained response rates similar to saline-maintained rates and significantly lower than rates maintained by cocaine (0.003-0.3 mg/kg/injection). Total session PTT intake was significantly lower than cocaine intake. In experiment 3, the discriminative stimulus effects of PTT (0.003-0.1 mg/kg, i.m.) were evaluated in monkeys (n = 3) trained to discriminate cocaine (0.2 mg/kg, i.m.) from saline (0.5 ml). PTT substituted for cocaine in a dose-dependent manner and was 0.5 to 1.0 log units more potent than cocaine. At the highest PTT dose, cocaine-appropriate responding was observed 8 to 24 hr after the injection. These results demonstrated that the long-acting indirect dopamine agonist PTT was effective in decreasing cocaine self-administration and in abuse liability testing showed a unique behavioral profile, not functioning as a reinforcer when substituted for cocaine and producing discriminative stimulus effects similar to cocaine.

The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in non-human primates. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-lever procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. Consistent with previous results in a variety of species, pentobarbital (0.56-17 mg/kg, IG) resulted in a dose-dependent substitution for the discriminative stimulus effects of ethanol, with an average ED50 value of 1.9 mg/kg. Administration of allopregnanolone (0.3-5.6 mg/kg, IV) also produced complete substitution for the discriminative stimulus effects of ethanol, with an ED50 value of 1.0 mg/kg. Plasma allopregnanolone levels 35 min following the administration of 3.0 mg/kg allopregnanolone ranged from 33 to 69 ng/ml. The ethanol-like discriminative stimulus effects of 1.0 mg/kg allopregnanolone (IV) were present for 60 min, with a return to complete water-appropriate responding at 90 min post-treatment. The results indicate that the endogenous neuroactive steroid allopregnanolone produces subjective effects in cynomolgus monkeys that are similar to ethanol. These findings suggest that changes in the endogenous levels of allopregnanolone could alter sensitivity to the subjective effects of ethanol.

The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (+/-)-5-aminocarbonyl-10,11-dihydro -5H-dibenzo-[a,d]cyclohepten-5,10-imine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low-affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.

Rats were trained in a two-lever procedure to discriminate either pentobarbital (10 mg/kg), ethanol (1.5 g/kg), diazepam (1 mg/kg), or lorazepam (1 mg/kg) from the no-drug condition. Consistent with previous reports, rats in the pentobarbital, ethanol, and diazepam training conditions all showed complete dose-dependent generalization to pentobarbital under test conditions, but rats trained to discriminate lorazepam did not. Administration of the neuroactive steroids 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THDOC) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) also produced complete generalization in rats trained to discriminate pentobarbital, ethanol, and diazepam, but not in rats trained to discriminate lorazepam. These results further indicate the specificity of the lorazepam training condition and are consistent with neurochemical data indicating that these neuroactive steroids are similar to barbiturates in modulating gamma-aminobutyric acid (GABA)A receptors. In the context of previous data, the results from the four training groups suggest that the discriminative-stimulus effects of the neuroactive steroids are sedative/anxiolytic in nature and probably mediated through a non-benzodiazepine GABAA site.

The ethanol-like discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists that act at the NMDA recognition site [(D)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene) and cis-4-phosphonomethyl-2-piperidine carboxylic acid] or within the NMDA associated cation channel [phencyclidine (PCP) and dizocilpine] were evaluated in rats trained to discriminate ethanol or PCP from vehicle in a two-lever discrimination procedure. Three groups of rats were trained to discriminate 1.0, 1.5 or 2.0 g/kg of ethanol from water and one group was trained to discriminate 1.5 mg/kg of PCP from saline. In the ethanol-trained groups, both PCP (1.0-5.6 mg/kg; i.p.) and dizocilpine (0.03-0.3 mg/kg; i.p.) completely substituted for ethanol in every rat tested, although the dizocilpine resulted in only partial substitution in rats trained to discriminate 1.0 g/kg of ethanol. As the training dose of ethanol increased, the potency of PCP and dizocilpine to substitute for ethanol increased. In contrast, CPPene (1-17 mg/kg; i.p.) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (5.6-17 mg/kg; i.p.) resulted in partial substitution for ethanol, with lower amounts of ethanol-appropriate responding as the training dose of ethanol increased. These data indicate that uncompetitive antagonism of NMDA neurotransmission at sites within the cation channel produce discriminative stimulus effects that are similar to those of ethanol, particularly to higher ethanol doses. Neither ethanol (0.5-1.5 g/kg; i.p.) nor CPPene (5.6 and 10 mg/kg) completely substituted for the discriminative effects of PCP. The asymmetrical generalizations between ethanol and PCP are discussed in terms of the mixed discriminative effects of ethanol.

Acquisition and retention of a delayed alternation task by rats genetically deficient in vasopressin (AVP) due to the homozygous occurrence of the Brattleboro diabetes insipidus (DI) gene (M520/DI) were compared to the response of rats that were heterozygous (M520/HZ) or normal (M520/N) with respect to the DI gene. No significant difference in the adaptation to the apparatus was observed between the groups. However, the rate at which the M520/DI rats acquired the alternation task was significantly slower than the acquisition rates of M520/HZ and M520/N rats. In addition, the maximum intertrial interval reached by the M520/DI rats was significantly shorter than the intertrial intervals reached by the M520/HZ and M520/N rats, indicating the ability to retain information was impaired in the M520/DI rats. These results are consistent with the hypothesis that AVP modulates the acquisition and retention of information for normal memory processes.