Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling

A major problem with current anti-depressant therapy is that it takes on average 6-7 weeks for remission. Since desensitization of serotonin (5-HT)_1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressants. The purpose of the present study was to test the hypothesis that estradiol accelerates fluoxetine-induced desensitization of 5-HT_1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) of rats, via alterations in components of the 5-HT_1A receptor signaling pathway. Ovariectomized rats were injected with estradiol and/or fluoxetine, then adrenocorticotropic hormone (ACTH) and oxytocin responses to a 5-HT_1A receptor agonist (+)-8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) were examined to assess the function of 5-HT_1A receptors in the PVN. Treatment with estradiol for either 2 or 7 days or fluoxetine for 2 days produced at most a partial desensitization of 5-HT_1A receptor signaling, whereas 7 days of fluoxetine produced full desensitization. Combined treatment with estradiol and fluoxetine for 2 days produced nearly a full desensitization, demonstrating an accelerated response compared to either treatment alone. With two days of combined treatments, estradiol prevented the fluoxetine-induced increase in 5-HT_1A receptor protein, which could contribute to the more rapid desensitization. Furthermore, EB treatment for 2 days decreased the abundance of the 35kD Gαz protein which could contribute to the desensitization response. We found two isoforms of Gαz proteins with molecular mass of 35 and 33kD, which differentially distributed in the detergent resistant microdomain (DRM) and in Triton X-100 soluble membrane region, respectively. The 35kD Gαz proteins in the DRM can be sumoylated by SUMO1. Stimulation of 5-HT_1A receptors with 8-OH-DPAT increases the sumoylation of Gαz proteins and reduces the 33kD Gαz proteins, suggesting that these responses may be related to the desensitization of 5-HT_1A receptors. Treatment with estradiol for 2 days also reduced the levels of the G-protein coupled estrogen receptor GPR30, possibly limiting to the ability of estradiol to produce only a partial desensitization response. These data provide evidence that estradiol may be effective as a short-term adjuvant to SSRIs to accelerate the onset of therapeutic effects.