Antipsychotic drug affinities at α2-adrenoceptor subtypes in post-mortem 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 affinities for alpha(2)-adrenoceptor subtypes in the human brain. We have assessed the ability of three classical and four 'atypical' antipsychotic drugs to displace binding of [H-3]RX821002 to alpha(2)-adrenoceptors in human post-mortem brain tissue. All seven drugs displaced radioligand from an apparent single site in the frontal cortex, consistent with the sole presence of the alpha(2A)-subtype in this region. In the caudate nucleus, all drugs except risperidone differentiated two sites, of which one was equivalent to the cortical alpha(2A)-subtype and the second, accounting for approximately two-thirds of specific radioligand binding, showed higher affinity for the antipsychotics. This second site, on the basis of prazosin's relatively high affinity, is consistent with an alpha(2B)-adrenoceptor identity. The new antipsychotic quetiapine showed the greatest selectivity for this receptor site; both quetiapine and clozapine had affinities for the alpha(2B) Site which were greater than their affinities for human D-2 dopamine receptors. The possible role of this site in the mechanisms underlying aspects of antipsychotic drug atypicality is discussed.