Participação dos receptores para esteróides ovarianos na ação da kisspeptina sobre neurônios dopaminérgicos e secreção de prolactina

Abstract

We have shown that kisspeptin stimulates prolactin (PRL) secretion in an estradiol-dependent manner through inhibition of dopaminergic terminals in the median eminence (ME). The effects of estradiol may occur via estrogen receptor (ER) or ER, but the role of these receptors in this mechanism has not been elucidated. Likewise, the role played by progesterone and its receptor (PR) in kisspeptin regulation of dopamine function and PRL secretion has not been demonstrated so far. Thus, we performed in vivo experiments in female rats to investigate the role of ER and PR on the effect of kisspeptin on PRL secretion and activity of dopaminergic terminals in the ME and neuro-intermediate lobe of the pituitary gland (NIL). Initially, we validated the use of tamoxifen, a selective estrogen receptor modulator (SERM) as an antagonist of the stimulatory effects of estradiol on PRL secretion. In subsequent experiments, ovariectomized (OVX) rats were treated with estradiol (OVX+E), estradiol and tamoxifen (OVX+ET), or the selective agonists for ER and ER, PPT (OVX+PPT) and DPN (OVX+DPN), respectively. Additionally, to investigate the involvement of progesterone on kisspeptin action, OVX+E rats were treated with progesterone (OVX+EP) or progesterone and RU-486 (OVX+EP+RU), a selective antagonist of PR. In all experiments, rats received i.c.v injections of kisspeptin-10 or vehicle and plasma PRL levels were determined in blood samples. Tamoxifen suppressed the estradiol-induced surge of PRL and blocked the stimulatory effect of kisspeptin on PRL release. Tamoxifen also prevented the kisspeptin-induced reduction of dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the ME. OVX+PPT rats displayed higher PRL response to kisspeptin compared with OVX+E rats, which was associated with a reduction of DOPAC levels in both the ME and NIL. By contrast, kisspeptin had no effect on OVX+DPN rats. In OVX+EP rats, in turn, progesterone treatment amplified PRL release induced by kisspeptin, which was associated with a marked decreased in both DA and DOPAC levels in the ME and NIL. These effects of kisspeptin were prevented in OVX+EP+RU rats. Thus, our data show for the first time that the permissive action of estradiol in the effects of kisspeptin on DA and PRL occur through ER but not ER. Moreover, the effects of kisspeptin are potentiated by progesterone via PR activation. These findings contribute to elucidation of the role played by ovarian steroids in kisspeptin regulation of DA and PRL.