Modulation of the arcuate nucleus–medial preoptic nucleus lordosis regulating circuit: A role for GABAB receptors

Abstract

Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-α complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release β-endorphin. Estradiol treatment induces activation/ internalization of MPN μ-opioid receptors (MOR) to inhibit lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABA B ) activity. We tested the hypothesis that ARH GABA B receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double label immunohistochemistry revealed expression of GABA B receptors in NPY, ERα and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABA B receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABA B receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of lordosis testing. Bilateral infusions of the GABA B receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol-induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB treated rats, bilateral CGP52432 infusions 30 minutes before behavior testing attenuated MOR internalization and facilitated lordosis. These results indicated that GABA B receptors were located within the lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of lordosis behavior. Although GABA B receptors positively influence estradiol signaling, they negatively regulate lordosis behavior since GABA B activity maintains the estradiol-induced inhibition.

Estradiol Upregulates Progesterone Receptor and Orphanin FQ Colocalization in Arcuate Nucleus Neurons and Opioid Receptor-Like Receptor-1 Expression in Proopiomelanocortin Neurons That Project to the Medial Preoptic Nucleus in the Female Rat

“…The unilateral guide cannulae were implanted using standard stereotaxic procedures [5, 27, 32]. The rats were anesthetized using 2–3% isoflurane in oxygen and injected with Carprofen (s.c. 5 mg/kg), an analgesic, prior to surgery.…”

“…Forty-eight hours after EB treatment, each animal was deeply anesthetized with isoflurane and transcardially perfused with chilled saline followed by perfusion with chilled 4% paraformaldehyde in Sorensen's phosphate buffer (pH 7.5) [5, 27, 32]. The brains were removed and postfixed overnight in 4% paraformaldehyde and then cryoprotected by immersion in 20% sucrose in a 0.1 M phosphate buffer solution (pH 7.5) and stored at 4°C [2, 3].…”

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female

“…1; reviewed in Micevych & Sinchak, 2013;Sinchak & Wagner, 2012). All of the steroid priming paradigms that facilitate lordosis converge to regulate the output of ARH β-endorphin (β-END) neurons that project to the MPN (Borgquist et al, 2013(Borgquist et al, , 2014Cheung & Hammer, 1995;Christensen, Dewing, & Micevych, 2011;Christensen & Micevych, 2012Dewing et al, 2007;Dewing, Christensen, Bondar, & Micevych, 2008;Long, Chhorvann, & Sinchak, 2012;Long et al, 2013Long et al, , 2014Micevych, Rissman, Gustafsson, & Sinchak, 2003;Mills, Sohn, & Micevych, 2004;Sanathara et al, 2011Sanathara et al, , 2014Sinchak et al, 2013;Sinchak & Micevych, 2001;Sinchak, Shahedi, Dewing, & Micevych, 2005; Fig. 1).…”

“…1; Dewing et al, 2007;Eckersell et al, 1998;Micevych et al, 2003;Mills et al, 2004;Sinchak & Micevych, 2001;Sinchak et al, 2005). Thus, we have optimized methods for determining whether hormonal or pharmacological manipulations that regulate sexual receptivity also regulate the activity of this ARH-MPN lordosis circuit Sanathara et al, 2011;Sinchak et al, 2013;Sinchak & Micevych, 2001). Although we have a good understanding that MPN MOP activity mediates hormonal regulation of the sexual receptive state of the rat, we know little about these MPN MOP neurons.…”

Estudo das eferências do núcleo pré-óptico medial para o núcleo ventromedial do hipotálamo em animais ooforectomizados pré-puberes.

“…Contudo, é um núcleo com efeitos opostos no comportamento, pois ao mesmo tempo em que age no controle da fase apetitiva devido às suas projeções para a área tegmental ventral [VTA], de onde origina eferências dopaminérgicas para o núcleo accumbens [ACB], que é uma região também envolvida na motivação do comportamento sexual (Kato , Sakuma, 2000), age inibindo o comportamento de lordose, por meio de projeções para o VMHvl (Takeo, Chiba , Sakuma, 1993). Isso ocorre, pois, além de ser responsável por realizar o planejamento comportamental e integrar a informação sensorial, este mesmo efetua a integração hormonal, controlando a receptividade da fêmea para que a cópula resulte em fecundação (Simerly , Swanson, 1988;Sinchak et al, 2013).…”