Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus

Selective serotonin reuptake inhibitors (SSRIs), such as Prozac®, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT1A) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT1A receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT1A receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT1A receptor signaling, but, in rats, these effects occur within 2 days; thus, estrogens or selective estrogen receptor modulators may serve as useful short-term tools to accelerate desensitization of 5-HT1A receptors in response to SSRIs if candidate estrogen receptor targets in the hypothalamus are identified. We found high levels of GPR30, which has been identified recently as a pertussis-toxin (PTX) sensitive G-protein-coupled estrogen receptor, in the hypothalamic paraventricular nucleus (PVN) of rats. Double-label immunohistochemistry revealed that GPR30 co-localizes with 5-HT1A receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-β-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT1A receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT1A receptor signaling in the PVN as measured by an attenuated oxytocin (by 29%) and ACTH (by 31%) response to DPAT. This study indicates that a putative extra-nuclear estrogen receptor, GPR30, may play a role in estradiol-mediated attenuation of 5-HT1A receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.