Abstract
The atypical antipsychotic drug clozapine interacts with multiple transmitter systems, among them the D4 subtype of dopamine receptors. PNU-96415E is chemically unrelated to clozapine and has its highest binding affinity for the D4 and 5-HT2Areceptors. In comparison to clozapine, PNU-96415E is weaker in binding to D1, D2, α1 and muscarinic receptors. PNU-96415E inhibited exploratory locomotor activity in mice and rats, and antagonized d-amphetamine-induced locomotor stimulation in rats. It antagonized apomorphine-induced cage climbing, and blocked head and body twitch produced by 5-HTP in mice. Like clozapine, but unlike haloperidol, PNU-96415E did not antagonize stereotypic behaviors produced by a high dose ofd-amphetamine or methylphenidate in rats and mice. PNU-96415E blocked conditioned avoidance in rats but produced no catalepsy, a pattern similar to clozapine but different from haloperidol. In rats trained to discriminate clozapine from saline injections, the stimulus effect generalized completely with PNU-96415E, but not haloperidol. This profile of pharmacological activities is consistent with that of an atypical antipsychotic and, as in the case with clozapine, the behavioral effects of PNU-96415E cannot be ascribed to a single receptor mechanism.
Footnotes
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Send reprint requests to: S. R. Franklin, CNS Research 7251-209-406, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001.
- Abbreviation:
- DS
- discriminative stimulus
- Received April 18, 1996.
- Accepted December 16, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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