Vol. 294, Issue 1, 296-301, July 2000

Coadministration of 5-Hydroxytryptamine_1A Antagonist WAY-100635 Prevents Fluoxetine-Induced Desensitization of Postsynaptic 5-Hydroxytryptamine_1A Receptors in Hypothalamus¹

Florence Serres², Nancy A. Muma, Daní K. Raap³, Francisca Garcia, George Battaglia and Louis D. Van de Kar

Loyola University of Chicago, Stritch School of Medicine, Department of Pharmacology, Maywood, Illinois

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-HT_1A receptors; whether blockade of somatodendritic 5-HT_1A autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT_1A receptors. WAY-100635 was tested at low doses (0.03-0.3 mg/kg), which antagonize somatodendritic 5-HT_1A autoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT_1A receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT_1A receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT_1A receptors 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-HT_1A receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT_1A receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT_1A receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT_1A 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-HT_1A receptor desensitization could involve post-translational modifications in the 5-HT_1A receptor-Gz protein-signaling cascade.