Negative regulation of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor gene expression by a gonadotropin-releasing hormoneagonist in the rat hypothalamus

There exists evidence for the presence of ultrashort loop feedback circuits of gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. It is, however, uncertain whether a similar mechanism is involved in the regu lation of GnRH gene expression in vivo, Furthermore, little is known about the regulation of GnRH receptor (GnRHR) expression in the brain. In the pre sent study, we examined the regulation of GnRH and its receptor gene expres sion by GnRH in vivo. A GnRH agonist, [D-Ala(6), des-Gly(10)]GnRH-ethylamid e (des-Gly GnRH), was administered by intracerebroventricular (i.c.v.) inje ction via the lateral ventricle of ovariectomized and estradiol (OVX + E)-t reated rats. The amounts of GnRH and GnRHR mRNA were measured in the preopt ic area (POA) and posterior mediobasal hypothalamus (pMBH) micropunch sampl es from individual rat brain slices by respective competitive reverse trans cription-polymerase chain reactions. The i.c.v. administration of des-Gly G nRH significantly decreased GnRH and GnRHR mRNA expression in a dose-and ti me-related manner: des-Gly GnRH (6 ng) suppressed GnRH and GnRHR mRNA expre ssion within 2 h, and the suppression was maintained without significant va riation until 8 h after treatment, Treatment with Antide, [N-Ac-D-NaI(2)(1) , pCl-D-Phe(2), D-PaI(3)(3), Lys(Nic)(5), D-Lys(Nic)(6), Lys(iPR)(8), D-Ala (10)]GnRH (10 ng), a potent GnRH antagonist, did not alter GnRH mRNA expres sion, but prevented des-Gly GnRH-induced suppression of GnRH mRNA expressio n. Antide alone decreased GnRHR mRNA expression, but failed to alter agonis t-induced suppression of GnRHR mRNA expression. These results demonstrate t he existence of an ultrashort loop feedback mechanism for GnRH gene express ion in the POA, along with homologous down-regulation of GnRHR mRNA express ion in the pMBH.