Differential regulation of 5-HT_1A receptor-G protein interactions in brain following chronic antidepressant Administration

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 [³⁵S]GTPγS 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 [³⁵S]GTPγS 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 [³⁵S]GTPγS 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 [³⁵S]GTPγS 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.