Seroquel: biochemical profile of a potential atypical antipsychotic

Abstract

Seroquel and the atypical antipsychotic clozapine were compared using a number of biochemical measures in rats which are indicative of potential antipsychotic activity and possible extrapyramidal side effect liability. Both in vitro and in vivo, these compounds are low potency D-2 dopamine (DA) receptor antagonists and are relatively more potent 5-HT2 antagonists than typical antipsychotic drugs. Seroquel also exhibited low affinity for D-1 DA receptors in vitro, but D-1 receptor occupancy was not detectable in vivo. Unlike clozapine, Seroquel lacks appreciable activity at either D-1 DA or muscarinic receptors. Following IP administration, both compounds produce similar elevations in DA metabolite concentrations. Following 1 month of daily administration, at doses which produce large increases in striatal DA metabolite concentrations, both Seroquel and clozapine fail, unlike typical antipsychotics, to increase the number of striatal D-2 receptors, but do decrease the number of 5-HT2 receptors in frontal cortex. ICI 204,636 produces a short-lasting increase in plasma prolactin levels, but these increases are much greater than those that are produced by clozapine. One day after 3 weeks of daily administration, tolerance, to the ability of Seroquel to elevate DA metabolite and plasma PRL concentrations is not observed. These biochemical observations are discussed with regard to the atypical profile of Seroquel in behavioral and electrophysiological studies.