POTENCY MISMATCH FOR BEHAVIORAL AND BIOCHEMICAL EFFECTS BY DOPAMINE RECEPTOR ANTAGONISTS - IMPLICATIONS FOR THE MECHANISM OF ACTION OF CLOZAPINE

Clozapine (3.8-60.0 mumol kg-1) did not produce any alterations in DOPA accumulation (following inhibition of cerebral aromatic L-amino acid decarboxylase) in the prefrontal cortex or in three regions of the neostriatum, i.e. the ventral, the dorso-lateral and the posterior regions, in the rat. In contrast, clozapine produced a reduction in the 5-HTP accumulation in all these brain areas, except for the prefrontal cortex. Raclopride (0.08-20.0 mumol kg-1) produced a marked increase in DOPA accumulation in all four brain regions and an increase in 5-HTP accumulation in the dorso-lateral neostriatum (2.5-20.0 mumol kg-1), but not in the other forebrain regions. Treatment with SCH-23390 (0.4-1.6 mumol kg-1) resulted in increased DOPA accumulation in the ventral and posterior parts of the neostriatum. No other changes in the DOPA or 5-HTP accumulation were seen with SCH-23390. Considering the doses of these three compounds needed for suppression of conditioned avoidance behavior and for the induction of cataleptic rigidity, it is concluded that raclopride produces an increased DA synthesis at much lower doses than those needed for behavioral effects. In contrast, the behavioral effects of SCH-23390 or clozapine precedes effects on brain DA synthesis on the dose-effect curve. In fact, the only biochemical effect of clozapine, which was observed in low, yet behaviorally active doses, was a decrease in forebrain 5-HTP accumulation. In conclusion, the present results demonstrate a mismatch, in different directions for raclopride and SCH-23390, as regards the doses needed to produce effects on brain dopamine synthesis and on behavior. Thus, the biochemical effects are seen with lower doses than the behavioral effects for the DA D2 receptor blocking agent, whereas the opposite relationship is the case for the DA D2 receptor antagonist. Taking these two DA receptor subtypes into consideration, the possibility should be considered that clozapine produces its antipsychotic-like behavioral effects on animal behavior primarily by a blockade of brain DA D1, rather than D2, receptors.