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

The radioligand [H-3]YM-09151-2 ((+/-)-cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylamino benzamide) was used to study the binding of various antipsychotic agents. Saturation experiments showed that [H-3]YM-09151-2 labelled a single population of binding sites in both the olfactory tubercle 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). Risperidone and thioridazine displaced [H-3]YM-09151-2 in a biphasic manner in both brain regions, and clozapine also produced biphasic displacement curves in the olfactory tubercle but not in the striatum. All other dopamine D2 receptor antagonists tested displaced [H-3]YM-09151-2 in a monophasic manner in both brain regions, in agreement with previously 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 thioridazine, risperidone and clozapine might discriminate between different affinity states and/or subtypes of the dopamine D2 receptor which may be different from the recently identified D2short and D2long receptors.