Differential regulation of 5-HT1A 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 [(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.
Hensler
Julie G
JG
Department of Pharmacology, University of Texas Health Science Center-San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. hensler@uthscsa.edu
D000639:Amitriptyline / Q000008:administration & dosage; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage; D019204:GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000378:metabolism
D000639:Amitriptyline; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D019204:GTP-Binding Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors