Agonist-stimulated GTPgamma[35S] binding to 5-HT(1A) receptors in human post-mortem brain

In this study, we have demonstrated that the technique of agonist-stimulated guanosine-5'-O-(3-[35S]thio)-triphosphate (GTPgamma[35S]) binding can be successfully used to study the functional activity of the human 5-HT(1A) receptor in post-mortem tissue. Full agonist and antagonist actions of ligands specific for this site have been shown. Utilising 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-fluorobenzamido]- ethyl-piperazine ([3H]MPPF), the affinity of several antipsychotics for the 5-HT(1A) receptor was determined; clozapine and quetiapine were found to have K(i) values at this receptor that, relative to their dopamine D(2) receptor affinities, indicated at least partial receptor occupancy at clinical doses. The agonist/antagonist activity of these two antipsychotics was studied using GTPgamma[35S] binding. Both compounds show partial agonism, and in addition, clozapine exhibited a larger degree of antagonism against 5-HT-stimulated binding than did quetiapine.