THE ROLE OF 5-HT2A RECEPTORS IN ANTIPSYCHOTIC ACTIVITY

The correlation between the clinical activity of antipsychotic agents and their affinity for the D-2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additi onal receptor systems. In particular, the high affinity of clozapine f or the 5HT(2A) receptor subtype has been suggested to contribute to it s reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-H T2A antagonist MDL 100,907 to explore the contribution of 5-HT2A recep tor blockade to antipsychotic activity. Biochemical, electrophysiologi cal and behavioral studies reveal that selective 5HT(2A) receptor anta gonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds prod ucing 5-HT2A receptor blockade are effective, in particular, against t he negative symptoms of schizophrenia.