Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration

Neuropsychopharmacology. 2002 May;26(5):565-73. doi: 10.1016/S0893-133X(01)00395-5.

Abstract

Changes in 5-HT(1A) receptor function or sensitivity following chronic antidepressant treatment may involve changes in receptor-G protein interaction. We have examined the effect of chronic administration of the SSRI fluoxetine or the tricyclic antidepressant amitriptyline on 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in serotonergic cell body areas, and cortical and limbic structures using quantitative autoradiography. Treatment of rats with fluoxetine, but not amitriptyline, resulted in an attenuation of 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the dorsal and median raphe nuclei. The binding of the antagonist radioligand [3H]MPPF to 5-HT(1A) receptor sites was not altered, suggesting that the observed changes in 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding were not due to changes in receptor number. Thus, the desensitization of somatodendritic 5-HT(1A) autoreceptors in the dorsal and median raphe following chronic SSRI treatment appears to be due to a reduced capacity of the 5-HT(1A) receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding was observed in any of the forebrain areas examined following chronic antidepressant treatment. Thus, changes in postsynaptic 5-HT(1A) receptor-mediated responses reported to follow chronic SSRI or tricyclic antidepressant administration most likely occur distal to receptor-G protein interaction, perhaps at the level of effector, or involving changes in neuronal function at the system or circuit level.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amitriptyline / administration & dosage
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Antidepressive Agents / metabolism
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Antidepressive Agents, Tricyclic / metabolism
  • Brain / drug effects*
  • Brain / metabolism*
  • Brain / physiology
  • Drug Administration Schedule
  • Fluoxetine / administration & dosage
  • GTP-Binding Proteins / metabolism*
  • GTP-Binding Proteins / physiology
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Injections, Intraperitoneal
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin / physiology
  • Receptors, Serotonin, 5-HT1
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / metabolism

Substances

  • Antidepressive Agents
  • Antidepressive Agents, Tricyclic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Amitriptyline
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • GTP-Binding Proteins