ANTIPSYCHOTIC DRUG AFFINITIES AT ALPHA(2)-ADRENOCEPTOR SUBTYPES IN POSTMORTEM HUMAN BRAIN

Although there is substantial interest in the possible role of alpha(2 )-adrenoceptors in the antipsychotic efficacy of clozapine, there has so far been no systematic investigation of antipsychotic drug affiniti es for alpha(2)-adrenoceptor subtypes in the human brain. We have asse ssed the ability of three classical and four 'atypical' antipsychotic drugs to displace binding of [H-3]RX821002 to alpha(2)-adrenoceptors i n human post-mortem brain tissue. All seven drugs displaced radioligan d from an apparent single site in the frontal cortex, consistent with the sole presence of the alpha(2A)-subtype in this region. In the caud ate nucleus, all drugs except risperidone differentiated two sites, of which one was equivalent to the cortical alpha(2A)-subtype and the se cond, accounting for approximately two-thirds of specific radioligand binding, showed higher affinity for the antipsychotics. This second si te, on the basis of prazosin's relatively high affinity, is consistent with an alpha(2B)-adrenoceptor identity. The new antipsychotic quetia pine showed the greatest selectivity for this receptor site; both quet iapine and clozapine had affinities for the alpha(2B) Site which were greater than their affinities for human D-2 dopamine receptors. The po ssible role of this site in the mechanisms underlying aspects of antip sychotic drug atypicality is discussed.