CI-943, a potential antipsychotic agent. I. Preclinical behavioral effects

Abstract

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2-c] pyrazolo[3,4-e]-pyrimidine) is a novel agent that is chemically unrelated to available antipsychotics and is not a dopamine receptor antagonist. Like available antipsychotics, CI-943 reduces spontaneous locomotion in mice and rats and inhibits compulsive cage climbing induced by apomorphine in mice at doses that do not produce ataxia. However, CI-943 enhances rather than inhibits the locomotor stimulant effects of d-amphetamine in mice and rats. Unlike dopamine antagonists, CI-943 does not affect stereotypy caused by apomorphine or amphetamine in rats. CI-943 displays an antipsychotic-like profile in conditioned avoidance tests, inhibiting one-way avoidance in rats at doses that do not impair escape and inhibiting continuous avoidance in rats and squirrel monkeys at doses that do not impair shock termination responding. Although high doses of CI-943 produce dystonic movements in haloperidol-sensitized monkeys, CI-943 differs from dopamine antagonists that produce extrapyramidal dysfunction in humans in that doses of CI-943 that are sufficient to inhibit avoidance responding in monkeys do not produce extrapyramidal dysfunction. Unlike dopamine antagonists that produce tardive dyskinesia, CI-943 administered repeatedly at high doses does not produce behavioral supersensitivity to dopamine agonists in rats. These results demonstrate that CI-943 resembles available antipsychotics in some preclinical behavioral tests commonly used to predict antipsychotic efficacy but differs from dopamine antagonists in tests predictive of dopamine receptor antagonism and antipsychotic-induced neurological dysfunction.