Estradiol induces partial desensitization of serotonin 1A receptor signaling in the paraventricular nucleus of the hypothalamus and alters expression and interaction of RGSZ1 and Gαz

• Published in: Neuropharmacology 2012-04, Vol.62 (5-6), p.2040-2049
• Main Authors: Creech, R.D., Li, Q., Carrasco, G.A., Van de Kar, L.D., Muma, N.A.
• Format: Article
• Language: English
• Subjects: 5-HT1A; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Desensitization; Dose-Response Relationship, Drug; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen; Female; GTP-Binding Protein alpha Subunits - metabolism; GTPase-Activating Proteins - metabolism; Membrane Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neuroendocrine; Oxytocin; Oxytocin - blood; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; Regulators of G protein signaling proteins; RGS Proteins; Serotonin Receptor Agonists - pharmacology; Signal Transduction - drug effects
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.01.001

Hyperactivity of hypothalamic–pituitary mediated hormone responses, such as to stimulation with a serotonin 1A (5-HT1A) receptor agonist, are a feature of depression which are normalized with clinical improvement during drug therapy. We previously reported that SSRIs induce desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) while estradiol benzoate (EB) produces a more rapid, partial desensitization. In the current study, time course and dose–response experiments demonstrated that two once daily doses of EB is the minimum needed to induce the desensitization response as indicated by 5-HT1A receptor-stimulated release of oxytocin and that 10 μg/kg/day EB produces the maximal response, a partial desensitization of approximately 40%. The effects of two once daily injections of 10 μg/kg/day EB on Gαz and RGSZ1 proteins were examined as components of the 5-HT1A receptor signaling system, which mediates the release of oxytocin and adrenocorticotropic hormone. RGSZ1 appears to be a major target for EB-mediated responses in the 5-HT1A receptor signaling system. A 55 kD membrane-associate RGSZ1 protein was greatly increased in the PVN and rest of the hypothalamus and moderately increased in the dorsal hippocampus and amygdala after EB treatment as well as after an acute dose of a 5-HT1A receptor agonist. These results suggest that EB is a candidate for adjuvant therapy with SSRIs to hasten the therapeutic response and that RGSZ1 is a major target of EB therapy which could be explored as a target for novel therapeutic approaches for the treatment of depression. ► 2 once daily doses of EB is the minimum to induce desensitization of 5-HT1A receptors. ► 10 μg/kg/day EB produces the Emax response partial desensitization of 5-HT1A receptors. ► EB greatly increased a 55 kD membrane-associate RGSZ1 protein in hypothalamus. ► EB increased a 55 kD membrane-associate RGSZ1 protein in amygdala & hippocampus. ► EB is a candidate for adjuvant therapy with SSRIs to hasten the therapeutic response.