Two-lever Drug Discrimination Procedure Research Articles

Drug Discrimination in (+)‐Epibatidine‐Trained Monkeys: Agonists and Antagonists Effects of Nicotinic Drugs

The behavioral effects of nicotinic agonists and antagonists were studied in squirrel monkeys using a two‐lever drug discrimination procedure. Monkeys (n=4) were trained to discriminate i.m. injections of 0.001 mg/kg (+)‐epibatidine (EPI)–a α4β2 selective nicotinic agonist that is pharmacologically similar and structurally distinct from nicotine (NIC)–from saline on a 10‐response fixed‐ratio schedule of stimulus‐termination. Results show that high efficacy nicotinic agonists [(+)‐EPI, (‐)‐EPI, NIC] substituted fully for (+)‐EPI, whereas the highest doses of other nicotinic agonists produced intermediate levels of (+)‐EPI‐like discriminative‐stimulus (SD) effects [varenicline (VAR), cytisine (CYT)] or did not substitute for (+)‐EPI (lobeline). Minor tobacco alkaloids produced full (nornicotine, anabasine, myosmine, anatabine), intermediate (anabaseine) or no (cotinine) (+)‐EPI‐like effects. Pretreatment studies with nicotinic antagonists show that: a) mecamylamine (non‐selective) unsurmountably antagonized (+)‐EPI's effects; b) dihydro‐β‐erthroidine (α4β2‐selective) surmountably (>3‐fold rightward shift) blocked (+)‐EPI's effects; and c) methyllycaconitine (α7 selective) and hexamethonium (peripherally‐restrictive) failed to modify the SD effects of (+)‐EPI. In further studies, pretreatment with the partial nicotine agonists VAR and CYT did not block the SD effects of (+)‐EPI, and in fact, shifted the (+)‐EPI dose‐effect curve to the left (>3‐10‐fold). These results suggest that the SD effects of (+)‐EPI are mediated through a α4β2 nicotinic receptor subtype at which the partial agonists VAR and CYT do not exert partial antagonist actions (supported by NIH DA031231).

Discriminative stimulus properties of mitragynine (kratom) in rats.

Mitragynine (MG) is the primary active alkaloid extracted from the leaves of Mitragyna speciosa or kratom and exhibits pharmacological activities mediated by opioid receptors. The plant has been traditionally used for its opium and psychostimulant-like effects to increase work efficiency or as a substitute in the self-treatment of opiate addiction. The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats. Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement. Rats acquired the MG discrimination (15.0mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0mg/kg, i.p.) stimulus. The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.

Discriminative stimulus properties of N-desmethylclozapine, the major active metabolite of the atypical antipsychotic clozapine, in C57BL/6 mice

N-desmethylclozapine (NDMC) is the major active metabolite of the atypical antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D2 and cholinergic muscarinic M1/M4 agonist, whereas clozapine is a weak dopamine D2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the typical antipsychotic drug haloperidol (dopamine D2 antagonist) and the atypical antipsychotic drug aripiprazole (D2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile.

Head‐twitch response in rodents induced by the hallucinogen 2,5‐dimethoxy‐4‐iodoamphetamine: a comprehensive history, a re‐evaluation of mechanisms, and its utility as a model

Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT(2) ) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals.

A comparison of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in DBA/2 and C57BL/6 inbred mice

Inbred mouse strain comparisons are an important aspect of pharmacogenetic research, especially in strains known to differ in regard to specific neurotransmitter systems. DBA/2 mice differ from C57BL/6 mice in terms of both functional and anatomical characteristics of dopamine systems. Given the importance of D2 antagonism in the action of antipsychotic drugs and in theories regarding schizophrenia (i.e. the dopamine hypothesis), this study compared the discriminative stimulus properties of the atypical antipsychotic drug clozapine (CLZ) in C57BL/6 and DBA/2 inbred mice. DBA/2 and C57BL/6 mice were trained to discriminate 2.5 mg/kg of CLZ from vehicle in a two-lever drug discrimination procedure and tested with a variety of antipsychotic drugs and selective ligands. Both strains of mice readily acquired the CLZ discrimination. The atypical antipsychotic drugs olanzapine and risperidone fully substituted for CLZ in both DBA/2 and C57BL/6 mice, but ziprasidone fully substituted only in the C57BL/6 mice. The typical antipsychotic drug haloperidol produced partial substitution for CLZ in the DBA/2 mice, and the dopamine agonist amphetamine required a higher dose to reduce response rates significantly in DBA/2 mice as compared with C57BL/6 mice. Antagonism of serotonergic (5-HT2A/2B/2C) receptors with ritanserin and alpha1-adrenergic receptors with prazosin engendered CLZ-appropriate responding only in the C57BL/6 mice. Thus, while serotonergic and alpha-adrenergic antagonism were shown to be important for CLZ's discriminative cue in C57BL/6 mice, none of the selective ligands produced CLZ-appropriate responding in DBA/2 mice. Differences in dopamine-mediated functions between the two strains of mice may explain some of the findings in this study.

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats

While the role of dextrorphan and dextromethorphan as N-methyl- d-aspartate (NMDA) receptor antagonists has received considerable research attention, their effects on nicotinic acetylcholine receptors (nAChR) has been less well characterized. Recent in vitro and in vivo research has suggested that these drugs noncompetitively block α3β4 ⁎, α4β2, and α7 nAChR subtypes and antagonize nicotine's antinociceptive and reinforcing effects. Both drugs were most potent at blocking α3β4 ⁎ AChR. This study investigated the effects of dextrorphan and dextromethorphan on nicotine's discriminative stimulus effects. Three groups of rats were trained in a two-lever drug discrimination procedure to discriminate 0.4 mg/kg s.c. nicotine from saline. Nicotine dose-dependently substituted for itself in all three groups. In contrast, when dextrorphan (group 1) or dextromethorphan (group 2) were injected i.p., neither substitution for nor antagonism of nicotine was observed for either drug. Since i.p. administration allows substantial metabolism of dextromethorphan to its parent compound dextrorphan, the two drugs were also tested following s.c. administration (group 3). Discrimination results were similar across both routes of administration, in that neither substitution nor antagonism occurred, however, s.c. administration reduced response rates to a much greater extent than did i.p. administration. Previous work suggests that β2 subunits are crucial for mediation of nicotine's discriminative stimulus effects and may play a role in its reinforcing effects, albeit other research suggests a role for α3β4 ⁎ nicotinic receptors in the latter. Our results suggest that α3β4 ⁎ nicotinic receptors do not play a major role in nicotine's discriminative stimulus effects. Further, they suggest that the role of cholinergic mediation of the behavioral effects of dextrorphan and dextromethorphan related to the abuse properties of nicotine may be minimal.

Increases in amphetamine-like discriminative stimulus effects of the abused inhalant toluene in mice

Toluene, an abused solvent, shares behavioral and pharmacological effects with abused depressant drugs. These effects include ethanol- and pentobarbital-like discriminative stimulus effects. There is also emerging evidence that this abused inhalant may share stimulus effects with abused central nervous system (CNS) stimulants. To further explore the discriminative stimulus effects of one abused inhalant, this experiment evaluated the amphetamine-like discriminative stimulus effects of toluene. Mice were trained to discriminate between d-amphetamine (1.0 mg/kg) and saline in a two-lever drug discrimination procedure in which responding was under the control of a fixed-ratio 15 schedule. Mice were tested after 10-min inhalation exposures to air or toluene (500-6,000 ppm) and stimulus generalization was examined at 0, 15, 30, 45, 60, and 75 min post-exposure. Concentration-related increases in amphetamine-lever responding were observed for amphetamine doses >0.56 mg/kg with full substitution occurring immediately after testing for 1.0 and 1.78 mg/kg. Partial amphetamine-lever responding was observed for all concentrations of toluene across the 75-min post-exposure test trials. Response rates that had decreased immediately after all toluene exposures recovered within 15-min post exposure. This partial substitution of toluene for amphetamine suggests that studies of the effects of abused solvents on brain dopaminergic systems need to be included in the study of possible CNS mechanisms.

Interaction of lobeline and nicotinic receptor ligands with the discriminative stimulus properties of cocaine and amphetamine

Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular and plasmalemmal monoamine transporters. Moreover, lobeline has been shown to alter the neurochemical and behavioral effects of psychostimulants. The present study determined the effect of lobeline and drugs selective for nicotinic receptors on the discriminative stimulus properties of low doses of cocaine (1.6 or 5.0 mg/kg) or d-amphetamine (0.3 mg/kg) in rats, using a standard two-lever drug discrimination procedure with food reinforcement. Nicotine substituted for both amphetamine and cocaine. The nicotinic receptor antagonists mecamylamine and hexamethonium did not substitute for or block the cocaine or amphetamine stimulus. In contrast, lobeline substituted for cocaine, but did not substitute for amphetamine. In antagonism tests, lobeline doses that did not substitute for cocaine decreased responding on the cocaine-paired levers. Surprisingly, lobeline did not alter the discriminative stimulus properties of amphetamine. This research further supports the supposition that nicotine, cocaine and amphetamine produce similar, but distinct subjective states. Furthermore, the present findings suggest that lobeline has a complex mechanism of action to disrupt the behavioral effects of drugs of abuse.

Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on ethanol discrimination in the rat

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine. The DRN- and sham-lesioned rats were trained to discriminate ethanol (1.0 g/kg) from saline in a standard two-lever drug discrimination procedure. Acquisition of ethanol discrimination and discrimination performance after consumption of lower doses of ethanol did not differ between the groups. In substitution tests, diazepam (0.5–2.5 mg/kg), a nonselective benzodiazepine receptor agonist, partially generalized from the ethanol cue in both groups. In contrast, m-chlorophenylpiperazine (0.1–0.9 mg/kg), a mixed 5-HT 1B/2C receptor agonist, did not mimic the ethanol cue. The drug decreased response rates in both groups, but this effect was more evident in the sham-lesioned group. A 5-HT 1A receptor agonist, 8-hydroxy-2-(di- n-propyloamino)-tetraline (0.05–0.4 mg/kg), did not produce significant increase in ethanol-appropriate responding in either group. These results may indicate that 5-HT neurons of the DRN are not critically involved in ethanol discrimination in the rat.

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice

The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice. To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice. Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer. As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment. These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

P.5.011 The selective NR2B antagonist Ro 25-6981 potentiates the effect of nicotine on locomotor activity and dopamine release in the nucleus accumbens

Dopamine (DA) D1 agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D1 agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D1 agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D1 agonist in rhesus monkeys (n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D1 antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01–1.7 mg/kg) fully substituted for cocaine in three of four animals (>80% cocaine-appropriate responding), while SKF 38393 (0.3–10 mg/kg) occasioned <50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D1 antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D1 agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D1 agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.

Modulation of cocaine's discriminative stimulus effects by dopamine D 1 agonists in rhesus monkeys

Dopamine (DA) D 1 agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D 1 agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D 1 agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D 1 agonist in rhesus monkeys ( n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D 1 antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01–1.7 mg/kg) fully substituted for cocaine in three of four animals (>80% cocaine-appropriate responding), while SKF 38393 (0.3–10 mg/kg) occasioned <50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D 1 antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D 1 agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D 1 agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.

Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.

The discriminative stimulus (DS) properties of the selective serotonin (5-HT) uptake inhibitor (SSRI), citalopram, are mediated by 5-HT2C receptors. Interestingly, the "atypical" antidepressants, mianserin and mirtazapine, behave as antagonists at 5-HT2C receptors. Herein, we evaluated the influence of mianserin and mirtazapine upon the DS effects of citalopram. In a two-lever drug discrimination procedure, rats initially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline were retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequently, generalization and antagonist studies were conducted with mianserin and mirtazapine. Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response rates. Their effective dose50s were 0.1 and 1.4 mg/kg, s.c., respectively. These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.

Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice

Mice of the C56BL/6J strain were trained to discriminate between nicotine (1.2 mg/kg) and saline in a two-lever drug discrimination procedure under a tandem variable-interval 60 s fixed-ratio 10 schedule of food reinforcement. Mice of the same strain were trained in conditioned taste aversion (CTA) experiments where drinking a saccharin or saline solution was paired with injection of nicotine or vehicle. During testing with both flavours presented simultaneously, a reduction in the intake of the nicotine-paired solution indicated CTA. The nicotine discrimination was acquired successfully and nicotine yielded a steep dose–response curve. The competitive nicotinic antagonist dihydro-β-erythroidine (DHβE, 0.6–3.0 mg/kg) shifted the dose–response for the discriminative stimulus effect of nicotine to the right; the α7 nicotinic receptor antagonist methyllycaconitine (MLA, 1.0–10 mg/kg) had no effect. The mice showed strong CTA to 2.0 mg/kg of nicotine and marginally to 0.6 and 1.2 mg/kg of nicotine. DHβE (3.0–5.6 mg/kg) attenuated the CTA while MLA (1.0–10 mg/kg) had no effect. These studies show that nicotine has discriminative and aversive stimulus properties in C57BL/6J mice and that the effects are mediated primarily by receptors sensitive to DHβE; there was no evidence for the involvement of α7 nicotinic receptors.

Drug discrimination: stimulus control during repeated testing in extinction.

Rats were trained, under a two-lever drug-discrimination procedure, to respond differentially depending upon whether lorazepam (1.0 mg/kg) or no injection had been administered before the session. Responses on the appropriate lever produced a food pellet under a modified fixed-ratio (FR) 10 schedule, in which the 10 responses had to be emitted consecutively. In reinforcement tests, completing an FR 10 on either lever produced a pellet. In extinction tests, stimulus changes paired with reinforcement occurred but no pellet was delivered. Training sessions were conducted between test sessions. Each of four extinction phases consisted of six tests preceded by one stimulus (e.g., lorazepam). Repeated exposures to extinction reduced response rates for all rats, but stimulus control, as inferred from either percentage of total responses or percentage of total FR 10s on the drug-appropriate lever, remained high. The percentage of total FR 10s measure was less subject to skewing under low-rate conditions than was the percentage of total responses measure and provided an evaluation of stimulus control in terms of meeting the consecutive response contingency. These results demonstrate a level of independence between response rate and stimulus control in drug discrimination, which has positive implications for the validity of interpreting discriminative effects of novel test conditions in well-trained animals, even when overall response rates are low.

Effects of drug discrimination history on anti-punishment properties of chlordiazepoxide in rats

Several studies have indicated that acquiring discriminative stimulus control for a certain anxiolytic drug influences its subsequent anti-conflict properties. To further elaborate on the question whether drug discrimination procedures affect behaviour in a conflict paradigm, a classical two-lever drug discrimination procedure was combined with an operant conflict procedure within the same animals. To this extent, rats were trained to discriminate the anxiolytic chlordiazepoxide (CDP, 30 mg/kg, po) from saline (SAL), and subsequently punished responding periods were introduced within the same session. In addition to the rats that were trained to discriminate CDP from vehicle, a group of rats was trained on a random relationship between CDP and the rewarded lever. CDP and alprazolam completely substituted for CDP, whereas mianserin did not. Responding during punished components in a session was increased by CDP and alprazolam, but not by mianserin in rats that were trained to discriminate CDP from vehicle and in randomly trained rats. The data indicate that rats can be reliably trained and tested in drug discrimination and conflict procedures within a single session and that CDP's discriminative stimulus does not alter its anti-conflict effects.

Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats.

Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. Generalization testing revealed full substitution with the atypical antipsychotics olanzapine (90.3% maximum generalization), sertindole (99.8%), and risperidone (87.1%) and partial substitution for quetiapine (seroquel, 66.4%) and the typical antipsychotics haloperidol (56.8%) and thioridazine (74.3%). Remoxipride (23.1%) and the typical antipsychotics chlorpromazine (27.9%) and fluphenazine (29.5%) did not reliably substitute for clozapine. In contrast to previous clozapine drug discrimination studies with higher training doses, the atypical antipsychotics olanzapine, sertindole, and risperidone reliably substituted for clozapine while typical antipsychotics did not. These results suggest that low-dose clozapine drug discrimination may be a more sensitive assay for distinguishing atypical from typical antipsychotic drugs.

(+)Amphetamine-Stimulus Generalization to an Herbal Ephedrine Product

We have previously demonstrated that a (+)amphetamine stimulus generalizes both to (−)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal (IP) administration of 1.0 mg/kg of (+)amphetamine (ED 50 = 0.4 mg/kg) from saline vehicle in a standard two-lever drug discrimination procedure, the present investigation shows that the (+)amphetamine stimulus generalizes to (+)amphetamine (ED 50 = 1.0 mg/kg) when administered via the intragastric (IG) route, and that (+)amphetamine appears about 2.5-fold less potent when administered via the IG route compared to the IP route. Likewise, (−)ephedrine (ED 50 = 10.8 mg/kg) and caffeine (ED 50 = 32.9 mg/kg) are also 2.5-fold less potent when administered via the IG route compared to their potency when administered via the IP route. The (+)amphetamine stimulus also generalizes to an IG-administered herbal preparation (i.e., Herbal XTC ®; the herbal preparation possesses an approximate potency roughly comparable to what might have been expected on the basis of its reported ephedrine and/or caffeine content. These results demonstrate, for the first time, that an ephedrine-containing herbal preparation can produce a (+)amphetamine-like effect in animals.

The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats

Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a twolever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine's discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.

Discriminative stimulus properties of alprazolam

The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40"-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-beta-carboline-3-carboxamide (FG-7142) and picrotoxin. These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.