TY - JOUR
T1 - Estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus is independent of estrogen receptor-beta
AU - Rossi, Dania V.
AU - Dai, Ying
AU - Thomas, Peter
AU - Carrasco, Gonzalo A.
AU - DonCarlos, Lydia L.
AU - Muma, Nancy A.
AU - Li, Qian
N1 - Funding Information:
Funding for this study was provided by NIMH Grant MH058448 (N.A.M.). The NIMH had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
PY - 2010/8
Y1 - 2010/8
N2 - Estradiol regulates serotonin 1A (5-HT1A) receptor signaling. Since desensitization of 5-HT1A receptors may be an underlying mechanism by which selective serotonin reuptake inhibitors (SSRIs) mediate their therapeutic effects and combining estradiol with SSRIs enhances the efficacy of the SSRIs, it is important to determine which estrogen receptors are capable of desensitizating 5-HT1A receptor function. We previously demonstrated that selective activation of the estrogen receptor, GPR30, desensitizes 5-HT1A receptor signaling in rat hypothalamic paraventricular nucleus (PVN). However, since estrogen receptor-beta (ERβ), is highly expressed in the PVN, we investigated the role of ERβ in estradiol-induced desensitization of 5-HT1A receptor signaling. We first showed that a selective ERβ agonist, diarylpropionitrile (DPN) has a 100-fold lower binding affinity than estradiol for GPR30. Administration of DPN did not desensitize 5-HT1A receptor signaling in rat PVN as demonstrated by agonist-stimulated hormone release. Second, we used a recombinant adenovirus containing ERβ siRNAs to decrease ERβ expression in the PVN. Reductions in ERβ did not alter the estradiol-induced desensitization of 5-HT1A receptor signaling in oxytocin cells. In contrast, in animals with reduced ERβ, estradiol administration, instead of producing desensitization, augmented the ACTH response to a 5-HT1A agonist. Combined with the results from the DPN treatment experiments, desensitization of 5-HT1A receptor signaling does not appear to be mediated by ERβ in oxytocin cells, but that ERβ, together with GPR30, may play a complex role in central regulation of 5-HT1A-mediated ACTH release. Determining the mechanisms by which estrogens induce desensitization may aid in the development of better treatments for mood disorders.
AB - Estradiol regulates serotonin 1A (5-HT1A) receptor signaling. Since desensitization of 5-HT1A receptors may be an underlying mechanism by which selective serotonin reuptake inhibitors (SSRIs) mediate their therapeutic effects and combining estradiol with SSRIs enhances the efficacy of the SSRIs, it is important to determine which estrogen receptors are capable of desensitizating 5-HT1A receptor function. We previously demonstrated that selective activation of the estrogen receptor, GPR30, desensitizes 5-HT1A receptor signaling in rat hypothalamic paraventricular nucleus (PVN). However, since estrogen receptor-beta (ERβ), is highly expressed in the PVN, we investigated the role of ERβ in estradiol-induced desensitization of 5-HT1A receptor signaling. We first showed that a selective ERβ agonist, diarylpropionitrile (DPN) has a 100-fold lower binding affinity than estradiol for GPR30. Administration of DPN did not desensitize 5-HT1A receptor signaling in rat PVN as demonstrated by agonist-stimulated hormone release. Second, we used a recombinant adenovirus containing ERβ siRNAs to decrease ERβ expression in the PVN. Reductions in ERβ did not alter the estradiol-induced desensitization of 5-HT1A receptor signaling in oxytocin cells. In contrast, in animals with reduced ERβ, estradiol administration, instead of producing desensitization, augmented the ACTH response to a 5-HT1A agonist. Combined with the results from the DPN treatment experiments, desensitization of 5-HT1A receptor signaling does not appear to be mediated by ERβ in oxytocin cells, but that ERβ, together with GPR30, may play a complex role in central regulation of 5-HT1A-mediated ACTH release. Determining the mechanisms by which estrogens induce desensitization may aid in the development of better treatments for mood disorders.
KW - Estradiol
KW - Estrogen receptors
KW - Mood disorders
KW - Neuroendocrine responses
KW - Recombinant adenovirus
KW - Serotonin receptors
KW - SiRNA
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U2 - 10.1016/j.psyneuen.2010.01.003
DO - 10.1016/j.psyneuen.2010.01.003
M3 - Article
C2 - 20138435
AN - SCOPUS:77954959473
SN - 0306-4530
VL - 35
SP - 1023
EP - 1033
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
IS - 7
ER -