A possible role of serotonin receptors in antidepressant drug action.

Summary Recently research into the mechanism of action of antidepres sant drugs has focused on mechanisms that could account for the delayed onset of therapeutic action. Chronic treatment with antidepressants elicits a delayed reduction in numbers of beta-adrenergic receptor binding sites as weil as norepinephrine sensitive adenylate cyclase. Besides catecholamines, serotonin mechanisms have been thought to playa major role in the ac tions of antidepressants. We have characterized two discrete serotonin receptors using ligand binding techniques. SI-recep tors are labelIed selectively by 3 H-serotonin and S2-receptors bind 3H-spiroperidol, while 3 H-LSD has equal affinities for SI and S2 receptors. Relative potencies of drugs in competing for SI-receptors show some correlations with effects on adenylate cyclase. Taken together with the regulation of SI-receptors by guanine nucleotides, a characteristic of adenylate cyclase linked receptors, we suggested, that S1-receptors may have some association with adenylate cyclase. S2"receptors, on the other hand, are not regulated by guanine nucleotides. Relative potencies of drugs in competing for S2 receptors parallel closely their ability to block serotonin related behavioral syndromes elicited by a variety of drugs. Thus the behavioral effects of most serotonin related drugs appear to be by S2-receptors. Chronic but not acute administration of both tricyclic antide pressants and monoamineoxidase inhibitors lowers the num bers of S2 -receptors. For most drugs these effects are more pronounced than the reduction in numbers of beta-adrenergic receptors. This effect is selective, since neuroleptics such as chlorpromazine and haloperidol are ineffective. Only a few antidepressants reduce numbers of SI -receptors and these ef fects