title: Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus.
abstract: Selective serotonin reuptake inhibitors (SSRIs), such as Prozac, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT(1A)) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT(1A) receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT(1A) receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT(1A) 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-HT(1A) 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-HT(1A) receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-beta-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT(1A) receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT(1A) 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-HT(1A) receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Qin
authors.forename: G A
authors.initials: GA
authors.lastname: Carrasco
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.forename: E J
authors.initials: EJ
authors.lastname: Filardo
authors.forename: E R
authors.initials: ER
authors.lastname: Prossnitz
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: L L
authors.initials: LL
authors.lastname: Doncarlos
authors.forename: N A
authors.initials: NA
authors.lastname: Muma
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D010052:Ovariectomy / Q000379:methods; D010121:Oxytocin / Q000097:blood; D037342:Pertussis Toxin / Q000494:pharmacology; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D001565:Benzoates; C520305:Gper1 protein, rat; D043562:Receptors, G-Protein-Coupled; D017366:Serotonin Receptor Agonists; C514340:estradiol-17-benzoate; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D004958:Estradiol; D010121:Oxytocin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D037342:Pertussis Toxin