Chronic administration of venlafaxine fails to attenuate 5-HT_1A receptor function at the level of receptor-G protein interaction

In this study venlafaxine was administered to rats at a low, moderate or high dose; for comparison, the selective serotonin reuptake inhibitor (SSRI) sertraline and the tricyclic antidepressant (TCA) amitriptyline were also included. We evaluated, using quantitative autoradiography, the effect of these antidepressant treatments on [³⁵S]GTPγS binding stimulated by the 5-HT_1A receptor agonist 8-OH-DPAT, a measure of the capacity of 5-HT_1A receptors to activate G proteins. Chronic administration of amitriptyline resulted in a marked increase in 5-HT_1A receptor-stimulated [³⁵S]GTPγS binding in the hippocampus which was accompanied by an increase in 5-HT_1A receptor number. 5-HT _1A receptor-stimulated [³⁵S]GTPγS binding in the hippocampus was also increased by chronic treatment with the highest dose of venlafaxine; 5-HT_1A receptor number, however, was not significantly altered. In serotonergic cell body areas (i.e. dorsal and median raphe nuclei), 5-HT_1A receptor-stimulated [³⁵S]GTPγS binding was not altered by chronic administration of amitriptyline, sertraline or venlafaxine. Chronic TCA treatment does not desensitize somatodendritic 5-HT_1A autoreceptor function. However, the lack of effect of chronic sertraline treatment on 5-HT_1A receptor-stimulated [ ³⁵S]GTPγS binding is in contrast to what has been observed previously following chronic administration of the SSRI fluoxetine, and suggests that different SSRIs may regulate somatodendritic 5-HT_1A autoreceptor function differently depending on their pharmacology. Our data also suggest that the desensitization of somatodendritic 5-HT_1A autoreceptors observed in electrophysiological studies following chronic venlafaxine administration is not at the level of receptor-G protein interaction. The hypothermic response in vivo to acute injection of 8-OH-DPAT was significantly attenuated following chronic treatment with venlafaxine or sertraline, but not amitriptyline.