RT Journal Article
SR Electronic
T1 Coadministration of 5-Hydroxytryptamine<sub>1A</sub>Antagonist WAY-100635 Prevents Fluoxetine-Induced Desensitization of Postsynaptic 5-Hydroxytryptamine<sub>1A</sub> Receptors in Hypothalamus
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 296
OP 301
VO 294
IS 1
A1 Florence Serres
A1 Nancy A. Muma
A1 Daní K. Raap
A1 Francisca Garcia
A1 George Battaglia
A1 Louis D. Van de Kar
YR 2000
UL http://jpet.aspetjournals.org/content/294/1/296.abstract
AB Treatment with selective serotonin reuptake inhibitors induces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)1A receptors in humans and rats. This study investigated whether fluoxetine-induced desensitization is due to overactivation of postsynaptic 5-HT1A receptors; whether blockade of somatodendritic 5-HT1A autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT1A receptors. WAY-100635 was tested at low doses (0.03–0.3 mg/kg), which antagonize somatodendritic 5-HT1Aautoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT1A receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT1A receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT1Areceptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (±)-8-hydroxy-2-dipropylaminoetetralin (50 μg/kg s.c.). WAY-100635 (0.03–0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT1A receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT1A receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT1A receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT1A receptors. Although previous studies indicate that injections of fluoxetine for 14 days produce a reduction of Gz protein levels in the hypothalamus, the levels of Gz proteins were not affected by either fluoxetine or WAY-100635. Alternative mechanisms mediating the initial stages of 5-HT1A receptor desensitization could involve post-translational modifications in the 5-HT1Areceptor-Gz protein-signaling cascade. The American Society for Pharmacology and Experimental Therapeutics