Antipsychotic drug affinities at α2-adrenoceptor subtypes in post-mortem human brain

Abstract

Although there is substantial interest in the possible role of α₂-adrenoceptors in the antipsychotic efficacy of clozapine, there has so far been no systematic investigation of antipsychotic drug affinities for α₂-adrenoceptor subtypes in the human brain. We have assessed the ability of three classical and four 'atypical' antipsychotic drugs to displace binding of [³H]RX821002 to α₂-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 α_2A-subtype in this region. In the caudate nucleus, all drugs except risperidone differentiated two sites, of which one was equivalent to the cortical α_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 α _2B-adrenoceptor identity. The new antipsychotic quetiapine showed the greatest selectivity for this receptor site; both quetiapine and clozapine had affinities for the α_2B site which were greater than their affinities for human D₂ dopamine receptors. The possible role of this site in the mechanisms underlying aspects of antipsychotic drug atypicality is discussed.