Antipsychotic drug affinities at alpha2-adrenoceptor subtypes in post-mortem human brain

Although there is substantial interest in the possible role of alpha2-adrenoceptors in the antipsychotic efficacy of clozapine, there has so far been no systematic investigation of antipsychotic drug affinities for alpha2-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 alpha2-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 alpha2A-subtype in this region. In the caudate nucleus, all drugs except risperidone differentiated two sites, of which one was equivalent to the cortical alpha2A-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 alpha2B-adrenoceptor identity. The new antipsychotic quetiapine showed the greatest selectivity for this receptor site; both quetiapine and clozapine had affinities for the alpha2B 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.