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Snyder SH, Peroutka SJ. 
“A Possible Role of Serotonin Receptors in Antidepressant Drug Action”. 
Pharmacopsychiat.. 1982;15:131-134.
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 well as norepinephrine sensitive adenylate cyclase. Besides catecholamines, serotonin mechanisms have been thought to play a major role in the ac tions of antidepressants. We have characterized two discrete serotonin receptors using ligand binding techniques. Sl-recep tars are labelled selectively by 3H-serotonin and S2-receptors bind 3H-spiroperidol, while 3H-LSD has equal affinities for Sl and S2 receptors. Relative potencies of drugs in competing for Sl-receptors show some correlations with effects on adenylate cyclase. Taken together with the regulation of Sl-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 Sl-receptors and these of fects are lesser than the reduction in S2-receptors. By contrast chronic treatment with antidepressants fails to alter numbers of dopamine, alpha-adrenergic or muscarinic cholinergic recap tars. Thus, it appears likely that reduction in numbers of S2 serotonin receptors as well as beta-adrenergic receptors are re lated to the antidepressant actions of drugs.
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