Joseph H. Porter

The role of muscarinic cholinergic receptors in the discriminative stimulus properties of clozapine in rats

The present study examined the role of muscarinic receptors in the discriminative stimulus properties of clozapine. One group of rats was trained to discriminate the atypical antipsychotic clozapine (CLZ, 5.0 mg/kg, i.p.) from vehicle in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (SCP, 0.125 mg/kg, i.p.) from saline. Complete cross-generalization was obtained for SCP in the CLZ-trained rats and for CLZ in the SCP-trained rats. The M1 muscarinic antagonist trihexyphenidyl substituted completely for both CLZ and SCP; however, the M2 antagonist BIBN 99 failed to substitute for either CLZ or SCP. In other substitution tests, the tricyclic antidepressant amitriptyline, the antihistamine promethazine, and cyproheptadine (5-hydroxytryptamine [5-HT]2A/5-HT2C, histamine, and muscarinic antagonist) substituted completely for CLZ and SCP. The tetracyclic antidepressant mianserin substituted completely in the CLZ-trained rats, but did not substitute for SCP. Compounds that produced partial substitution included the tricyclic antidepressant imipramine, the anxiolytic chlordiazepoxide, and the antipsychotic thioridazine. Other compounds tested only in the CLZ-trained rats that failed to produce reliable CLZ-appropriate responding included N-methyl-D-aspartic acid (NMDA, selective agonist for glutamate receptors), metergoline (5-HT2A/5-HT2C antagonist), propranolol (beta noradrenergic antagonist), and phentolamine (alpha noradrenergic antagonist). All of the compounds that produced CLZ-appropriate responding (except for mianserin) display high binding affinities for muscarinic cholinergic receptors. The results of the present study demonstrated that muscarinic receptors (especially M1) play an important role in the mediation of the discriminative stimulus properties of CLZ in rats, and provide additional support for the importance of CLZs anticholinergic properties as part of its unique profile as an atypical antipsychotic.

Acquisition of schedule-induced polydipsia in the Mongolian gerbil.

Abstract Three food-deprived Mongolian gerbils reliably displayed schedule-induced polydipsia when fixed-time food schedules were increased to 3-min interpellet intervals. No polydipsia was evident with shorter interpellet intervals. These data further extend the species generality of schedule-induced polydipsia, and indicate the importance of systematic variation of relevant variables before concluding that a given species does not display schedule-induced polydipsia.

Effects of four antipsychotics on punished responding in rats

In Experiment 1, the benzodiazepine chlordiazepoxide (CDP), two typical antipsychotics, haloperidol (HAL) and chlorpromazine (CPZ), and the atypical antipsychotic clozapine (CLZ) were evaluated for antipunishment effects in rats in a modified Geller-Seifter conflict procedure [MULT fixed interval (FI) 60-s, fixed ratio (FR) 1 (food + shock)]. In Experiment 2, CDP and thioridazine (THD) were similarly tested. CLZ (2.5 and 5.0 mg/kg), but not HAL, CPZ, or THD, selectively increased punished responding, although the magnitude of effect was smaller than that observed for CDP. Possible serotonergic mechanisms for CLZs action in this model and the possible importance of serotonergic activity for the development of other atypical antipsychotic drugs are discussed.

Serotonergic drugs do not substitute for clozapine in clozapine-trained rats in a two-lever drug discrimination procedure

The atypical neuroleptic clozapine has been shown to have cue properties in two-lever drug discrimination procedures. Although it has been demonstrated that clozapine acts at several types of receptors in vitro and in vivo, including dopamine, serotonin [5-hydroxytryptamine (5-HT)], and acetylcholine receptors, the mechanism of action for its discriminative stimulus properties has not yet been determined. The present study examined the effects of haloperidol (D2 dopamine antagonist), ritanserin (5-HT2 antagonist), 1-alpha H,3-alpha,5-alpha H-tropan-3yl-3,5-dichlorobenzoate (MDL 72222) (5-HT3 antagonist), and buspirone (5-HT1A agonist) in stimulus substitution tests with rats trained to discriminate clozapine (5.0 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure under a fixed ratio 30 schedule of food reinforcement. Analysis of the results revealed that, while clozapine produced dose-dependent responding on the clozapine lever, haloperidol and the three serotonin drugs failed to produce full substitution for clozapine at any of the doses tested. These results suggest that the discriminative stimulus properties are not mediated by D2 dopamine receptor blockade, antagonism at 5-HT2 or 5-HT3 receptors, or agonistic activity at 5-HT1A receptors. The neural basis of clozapines discriminative stimulus properties has not yet been determined.

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

Abstract  Rationale: Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. Objectives: The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. Methods: Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. Results: 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. Conclusions: 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.

Pimozide mitigates excessive running in the activity-stress paradigm

The present study investigated the role of dopamine in the maintenance of behaviors observed in the activity-stress paradigm. In Experiment 1, several doses (0, 0.125, 0.25, 0.50, and 1.0 mg/kg) of the dopamine D2-receptor blocker, pimozide, were administered to rats maintained on an ad lib feeding schedule. Results indicated that 0.25 mg/kg pimozide did not disrupt running activity when compared to control animals. In Experiment 2, injections of either 0, 0.25, or 0.50 mg/kg pimozide were given every 12 hours to rats subjected to the activity-stress paradigm. Although 0.25 mg/kg pimozide had no effect on dark-phase activity, it significantly suppressed light-phase activity and subsequently increased the number of survivors in the paradigm. It was concluded that dopamine plays a role in maintaining high running levels in the activity-stress paradigm.

Adjunctive behavior in the Mongolian gerbil

Abstract In Experiment 1, only one of five food-deprived gerbils displayed schedule-induced polydipsia when 45 mg food pellets were delivered according to a fixed-time 60-sec food schedule. However, in Experiment 2, three of four gerbils developed schedule-induced wheel running on the fixed-time 60-sec food schedule. These data extend the generality of adjunctive behaviors to another species, but also indicate that there are species differences in how readily some types of adjunctive behaviors are displayed.

Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine

Abstract The present study was conducted to determine if the putative atypical antipsychotic olanzapine could be established as a discriminative stimulus in rats. Seven rats were successfully trained to discriminate olanzapine (0.5 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure (mean number of acquisition sessions=39.3). Generalization testing with olanzapine (0.0625–2.0 mg/kg) yielded an ED50 of 0.170 mg/kg (95% confidence interval=0.118–0.246 mg/kg). The atypical antipsychotic clozapine (0.156–10.0 mg/kg) fully substituted for olanzapine in all rats at the 2.5 mg/kg dose with 99.0% drug-lever responding, in six rats at the 0.625 mg/kg dose, and in five rats at the 1.25 and 5.0 mg/kg doses (ED50=0.259 mg/kg, 95% confidence interval=0.089–0.755 mg/kg). This study is the first demonstration that rats can be trained to discriminate olanzapine from vehicle in a two-lever drug discrimination procedure and that the olanzapine discrimination cue generalizes to clozapine.

Schedule-induced polydipsia in the guinea pig

Abstract Two of three food-deprived guinea pigs displayed schedule-induced polydipsia when 45 mg food pellets were delivered according to a fixed-time 1-min food schedule. Both animals displayed the typical postpellet pattern of adjunctive drinking. These data extend the generality of schedule-induced polydipsia to a new species.

Sources of control over schedule-induced drinking produced by second-order schedules of reinforcement.

Abstract In Experiment 1, schedule-induced polydipsia was studied in rats reinforced by both simple and second-order fixed-interval 1 min schedules while session length, position of the drinking tube, and magnitude of the pellet reward were varied. Pellet-induced drinking decreased with successive transitions from simple to second-order schdules; however, drinking did not follow stimuli associated with pellet delivery until the reward magnitude was raised from 1 to 5 pellets. Neither session length nor tube position affected drinking. Poststimulus drinking received closer analysis in Experiment 2, where tandem, nonpaired and delayed or simultaneous paired brief stimulus second-order schedules, which were either fixed or variable, assigned large pellet magnitudes to rats. No evidence of adjunctive, stimulus-induced drinking was found. Occasions of drinking during poststimulus intervals were classified as either resumption of postpellet drinking or as low-rate terminal behavior which was unaffected by pairing relations between stimuli and pellets or by schedule class. No support was found for either discriminative or conditioned stimulus interpretations of schedule-induced polydipsia.