The role of 5-HT2A receptors in antipsychotic activity

Abstract 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 additional receptor systems. In particular, the high affinity of clozapine for the 5HT 2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT 2A antagonist MDL 100,907 to explore the contribution of 5-HT 2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT 2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT 2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.