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

Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-alpha complexes with and signals through the metabotropic glutamate receptor-la stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release beta-endorphin. Estradiol treatment induces activation/internalization of MPN mu-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, ER alpha 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 min 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. Published by Elsevier Inc.