Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 preventsfluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A)receptors in hypothalamus

Treatment with selective serotonin reuptake inhibitors induces a desensitiz ation of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)(1A) receptors in humans and rats. This study investigated whether fluoxetine-induced des ensitization is due to overactivation of postsynaptic 5-HT1A receptors; whe ther blockade of somatodendritic 5-HT1A autoreceptors accelerates this dese nsitization; 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-HT1A autorecept ors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely b locks postsynaptic 5-HT1A receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicato rs of hypothalamic 5-HT1A receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT1A receptors but th ree daily injections of fluoxetine produced a partial desensitization of th e hormone responses to (+/-)-8-hydroxy-2-dipropylaminoetetralin (50 mu g/kg s.c.). WAY-100635 (0.03-0.3 mg/kg) did not accelerate or potentiate the fl uoxetine-induced desensitization of 5-HT1A receptors. However, WAY-100635 a t a dose that completely blocks postsynaptic 5-HT1A receptors (1.0 mg/kg) c ompletely prevented the fluoxetine-induced desensitization of 5-HT1A recept ors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT1A rec eptors. Although previous studies indicate that injections of fluoxetine fo r 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 de sensitization could involve post-translational modifications in the 5-HT1A receptor-Gz protein-signaling cascade.