Neuroleptics and conditional discrimination tasks: cholinergic mediation of the accuracy- and response rate-altering effects of chlorpromazine and clozapine but not haloperidol.

The effects of the neuroleptic compounds clozapine, chlorpromazine and haloperidol were examined alone and in combination with the muscarinic cholinergic agonist oxotremorine in pigeons responding under a fixed-consecutive-number schedule. Under this procedure, nine or more consecutive responses on one response key followed by a single response on a second response key produced 3sec access to grain. In one component of this schedule (FCN 9-SD), an external discriminative stimulus was presented following the completion of the response requirement on the first response key, whereas no stimulus change was programmed in the other component (FCN 9). When administered alone, clozapine (0.1-5.6mg/kg) and chlorpromazine (3.0-170mg/kg) decreased accuracy (i.e. increased the mean number of response runs per reinforcer) under the FCN 9 at doses that had no effect under the FCN 9-SD. In contrast, haloperidol (0.03-1.7mg/kg) and oxotremorine (0.001-0.1mg/kg) had no effect on accuracy under either variant of the FCN schedule. Under both variants of the FCN schedule, clozapine, chlorpromazine, haloperidol and oxotremorine produced dose-related decreases in rates of responding. When administered in combination, oxotremorine (0.01 and 0.03mg/kg) antagonized the accuracy- and response rate-decreasing effects of both clozapine and chlorpromazine. Although neither haloperidol or oxotremorine decreased accuracy when administered alone, these drugs produced large decreases in accuracy when administered in combination. In most instances, the magnitude of these decreases in accuracy was larger than those obtained following the administration of clozapine or chlorpromazine. The effects of the co-administration of oxotremorine and haloperidol on rate of responding were generally additive. These findings indicate that both the accuracy- and response rate-decreasing effects of clozapine and chlorpromazine are, in part, mediated by their antagonist actions at muscarinic cholinergic receptors. In addition, the finding that the co-administration of haloperidol and oxotremorine decreased accuracy provides support at the behavioral level for an interaction of the dopaminergic and cholinergic systems.