Chronic administration of venlafaxine fails to attenuate 5-HT1A 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]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT, a measure of the capacity of 5-HT1A receptors to activate G proteins. Chronic administration of amitriptyline resulted in a marked increase in 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus which was accompanied by an increase in 5-HT1A receptor number. 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus was also increased by chronic treatment with the highest dose of venlafaxine; 5-HT1A receptor number, however, was not significantly altered. In serotonergic cell body areas (i.e. dorsal and median raphe nuclei), 5-HT1A receptor-stimulated [35S]GTPgammaS binding was not altered by chronic administration of amitriptyline, sertraline or venlafaxine. Chronic TCA treatment does not desensitize somatodendritic 5-HT1A autoreceptor function. However, the lack of effect of chronic sertraline treatment on 5-HT1A receptor-stimulated [35S]GTPgammaS 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-HT1A autoreceptor function differently depending on their pharmacology. Our data also suggest that the desensitization of somatodendritic 5-HT1A 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.
Rossi
Dania V
DV
Department of Pharmacology, University of Texas Health Science Center-San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Valdez
Marisela
M
Gould
Georgianna G
GG
Hensler
Julie G
JG
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000008:administration & dosage*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D000069470:Venlafaxine Hydrochloride
D003511:Cyclohexanols; D043562:Receptors, G-Protein-Coupled; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D000069470:Venlafaxine Hydrochloride