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

Changes in 5-HT1A 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-HT1A receptor-stimulated [S-35]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-HT1A receptor-stimulated [S-35]GTPgammaS binding in the dorsal and median raphe-nuclei. The binding of the antagonist radioligand [H-3]MPPF to 5-HT1A receptor sites was not altered, suggesting that the observed changes in 5-HT1A receptor-stimulated [S-35]GTPgammaS binding were not due to changes in receptor number. Thus, the desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal and median raphe following chronic SSRI treatment appears to be due to a reduced capacity of the 5-HT1A receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT1A receptor-stimulated [S-35]GTPgammaS binding was observed in any of the forebrain areas examined following chronic antidepressant treatment. Thus, changes in postsynaptic 5-HT1A 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. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.