Original Investigations

Psychopharmacology

, Volume 99, Issue 1, pp 64-69

Sertraline-induced desensitization of the serotonin 5HT-2 receptor transmembrane signaling system

  • Elaine Sanders-BushAffiliated withDepartments of Pharmacology and Psychiatry, Vanderbilt University School of Medicine
  • , Marsha BreedingAffiliated withDepartments of Pharmacology and Psychiatry, Vanderbilt University School of Medicine
  • , Karen KnothAffiliated withDepartments of Pharmacology and Psychiatry, Vanderbilt University School of Medicine
  • , Manami TsutsumiAffiliated withDepartments of Pharmacology and Psychiatry, Vanderbilt University School of Medicine

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Abstract

Sertraline is a new, selective serotonin (5HT) uptake inhibitor with antidepressant activity. The effect of chronic administration of sertraline on 5HT-2 receptors in rat cortex was compared with that of the tricyclic antidepressant, amitriptyline. 5HT-2 receptors were evaluated in binding assays using [3H]-ketanserin and in functional assays of transmembrane signaling, hydrolysis of phosphoinositides. The daily injection of 17 mg/kg sertraline induced a desensitization of 5HT-2-mediated phosphoinositide hydrolysis after 28, but not 21, days. The administration of 1.2 mg/kg/day via continuous release pumps caused a more rapid desensitization. Amitriptyline administered chronically also produced a densensitization of the 5HT-2-mediated phosphoinositide hydrolysis response. A decrease in the density of 5HT-2 binding sites accompanies the functional desensitization after amitriptyline, but changes in 5HT-2 binding sites were not detected after chronic sertraline administration. Studies of the mechanism of action of sertraline show that the desensitization of the phosphoinositide hydrolysis response is homologous in nature, and that it is not secondary to changes in the synthesis of precursor lipids. Other possibilities such as alterations in coupling efficiency or in the activity of effector enzymes are currently being considered. The present results suggest a new postsynaptic action of antidepressant drugs at central 5HT-2 receptors (i.e., changes in 5HT-2 signal transduction at a site distal to the cell surface binding site) and illustrate the importance of studies of receptor signaling pathways to complement radioligand binding.

Key words

Antidepressive agents Amitriptyline Serotonin receptors Serotonin Phosphoinositides Sertraline