Coadministration of 5-Hydroxytryptamine_(1A) Antagonist WAY-100635 Prevents Fluoxetine-Induced Desensitzation of Postsynaptic 5-Hydroxytryptamine_(1A) Receptors in Hypothalamus

摘要

Treatment with selective serotonin reuptake inhibitors induces a desensitizationof hyypotnalamic 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 bouple 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 (1mg/kg),which completely blocks postsynaptic 5-HT_(1A) receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (conrticotropin) were measured as peripheral indicatiors of hypothalamic 5-HT_(1A) receptor function. Daily injections of fluoxetine (10mg/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 #mu#g/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)com pletely prevented the fluoxetine-induced desensitization of 5-HT_(1A) receptors. These data demonstrate that at least 3 days of fluoxeine exposure is required to produce a homologous desnesitization of hypothalamic 5-HT_(1A) receptors. Although previous studies indicate that injections of fluoxetine for 14 days produce a reduciton 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 protien-signaling cascade.