Seroquel was compared to clozapine and several other antipsychotic agents in tests predictive of antipsychotic activity or extrapyramidal symptoms. In the conditioned avoidance test in squirrel monkeys as well as several paradigms using apomorphine or amphetamine-induced behavioral alterations, seroquel displayed the profile of a drug with potential antipsychotic activity. In these paradigms the potency of seroquel was somewhat less than clozapine in rodent tests, while the reverse was true in higher species, i.e. monkeys, cats. In tests designed to evaluate the propensity to induce EPS or tardive dyskinesia, for example, the production of dyskinetic reactions in haloperidol-sensitized cebus monkeys, seroquel displayed a profile similar to clozapine and disparate from typical antipsychotic drugs. In drug-naive cebus monkeys seroquel sensitized significantly fewer monkeys than haloperidol and the dyskinetic reactions were of significantly less intensity. It is anticipated that this novel antipsychotic agent will have a significantly reduced propensity to produce extrapyramidal symptoms and tardive dyskinesia than typical antipsychotics.

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Extracellular single unit recording techniques were employed to compare the effects of seroquel with the reference antipsychotic (AP) agents clozapine and haloperidol in electrophysiological tests that may predict AP activity. Seroquel and clozapine were differentially more active in reversing the inhibitory actions of d-amphetamine on mesolimbic (A10) than nigrostriatal (A9) dopamine (DA)-containing neurons, whereas haloperidol exhibited the opposite selectivity. In cell population studies, acute treatment with seroquel and clozapine selectively increased the number of spontaneously active A10 DA cells, which was found to correlate with the ability of both these drugs to cause depolarization inactivation (DI) of A10 DA cells following repeated (28 day) administration. This profile of activity was unlike that of haloperidol, which acutely caused a nonselective increase in the number of active A9 and A10 DA cells, associated with the ability of this agent to cause DI of both A9 and A10 DA cells after repeated treatment. Since DI of A10 DA cells may be correlated with AP efficacy whereas DI of A9 DA cells may predict the ability of an AP to cause extrapyramidal side effects (EPS) and tardive dyskinesia (TD), seroquel, like clozapine, may be an atypical AP with a reduced likelihood for producing EPS/TD.

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