BIPHASIC DISPLACEMENT OF [H-3] YM-09151-2 BINDING IN THE RAT-BRAIN BYTHIORIDAZINE, RISPERIDONE AND CLOZAPINE, BUT NOT BY OTHER ANTIPSYCHOTICS

The radioligand [H-3]YM-09151-2 lpyrrolidin-3-yl)-5-chloro-2-methoxy-4 -methylamino benzamide) was used to study the binding of various antip sychotic agents. Saturation experiments showed that [H-3]YM-09151-2 la belled a single population of binding sites in both the olfactory tube rcle and the striatum (dissociation constants (K(D)): 36 +/- 3 pM and 26 +/- 2 pM, respectively). The total number of binding sites (B(max)) was greater in the striatum than in the olfactory tubercle (18.1 +/- 1.8 fmol/mg tissue and 5.3 +/- 0.9 fmol/mg tissue respectively). Rispe ridone and thioridazine displaced [H-3]YM-09151-2 in a biphasic manner in both brain regions, and clozapine also produced biphasic displacem ent curves in the olfactory tubercle but not in the striatum. All othe r dopamine D2 receptor antagonists tested displaced [H-3]YM-09151-2 in a monophasic manner in both brain regions, in agreement with previous ly published data. Biphasic displacement did not appear to result from interactions with either the dopamine D3, dopamine D4, 5-HT2, 5-HT1C or the 5-HT1A receptor binding sites. It is suggested that thioridazin e, risperidone and clozapine might discriminate between different affi nity states and/or subtypes of the dopamine D2 receptor which may be d ifferent from the recently identified D2short and D2long receptors.