Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a

Abstract

In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E 2 ), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor ␤ (ER␤)-specific agonist, and to a lesser extent 17␣-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ER␣ (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E 2 or DPN, providing functional evidence that ER␤ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ER␤ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved.

Glutamate released in the preoptic area during sexual behavior controls local estrogen synthesis in male quail

“…Pharmacological studies have not yet determined the brain areas where rapid actions of estrogens modulate male quail sexual motivation; they only tested effects of peripheral (Cornil et al, 2006a; Cornil et al, 2006b) or intracerebroventricular injections (Seredynski et al, 2015; Seredynski et al, 2013). In rodents, the BNST appears to contribute more to the preparation for mating than to copulation per se (Hull and Dominguez, 2006).…”

Non-ovarian aromatization is required to activate female sexual motivation in testosterone-treated ovariectomized quail

“…The effects of estrogens on this aspect of sexual behavior seem to be even more prominent than the effects on the full sexual response expressed by crouching behavior suggesting a higher sensitivity to estrogenic activation. Future work should determine if as is the case in males (Seredynski et al, 2015; Seredynski et al, 2013), these effects are mediated by fast effects of estrogens initiated at the cell membrane or depend like consummatory sexual responses on slower genomic actions of the steroid.…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Interestingly, some of these membrane-initiated actions of estradiol are given by the interaction between ERs and other receptors, such as metabotropic glutamate receptors (Boulware, 2005;Boulware et al, 2013;Dewing et al, 2007;Kuo et al, 2010b;Seredynski et al, 2015) or IGF-1 receptor (Mendez et al, 2006(Mendez et al, , 2003.…”