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.