Kisspeptin Stimulation of Prolactin Secretion Requires Kiss1 Receptor but Not in Tuberoinfundibular Dopaminergic Neurons

Abstract

Kisspeptin has been shown to stimulate prolactin secretion. We investigated whether kisspeptin acts through the Kiss1 receptor (Kiss1r) to regulate dopamine and prolactin. Initially, we evaluated prolactin response in a Kiss1r-deficient mouse line, in which Kiss1r had been knocked into GnRH neurons (Kiss1r−/−R). Intracerebroventricular kisspeptin-10 (Kp-10) increased prolactin release in wild-type but not in Kiss1r−/−R female mice. In ovariectomized, estradiol-treated rats, the Kiss1r antagonist kisspeptin-234 abolished the Kp-10–induced increase in prolactin release but failed to prevent the concomitant reduction in the activity of tuberoinfundibular dopaminergic (TIDA) neurons, as determined by the 3,4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence. Using whole-cell patch clamp recordings in juvenile male rats, we found no direct effect of Kp-10 on the electrical activity of TIDA neurons. In addition, dual-label in situ hybridization in the hypothalamus of female rats showed that Kiss1r is expressed in the periventricular nucleus of the hypothalamus (Pe) and arcuate nucleus of the hypothalamus (ARC) but not in tyrosine hydroxylase (Th)–expressing neurons. Kisspeptin also has affinity for the neuropeptide FF receptor 1 (Npffr1), which was expressed in the majority of Pe dopaminergic neurons but only in a low proportion of TIDA neurons in the ARC. Our findings demonstrate that Kiss1r is necessary to the effect of kisspeptin on prolactin secretion, although TIDA neurons lack Kiss1r and are electrically unresponsive to kisspeptin. Thus, kisspeptin is likely to stimulate prolactin secretion via Kiss1r in nondopaminergic neurons, whereas the colocalization of Npffr1 and Th suggests that Pe dopaminergic neurons may play a role in the kisspeptin-induced inhibition of dopamine release.

Kisspeptin and Prolactin

“…At first look, these experiments produced somewhat contradictory data. We observed that ICV kisspeptin-10 increased prolactin release in control wild-type mice but failed to do so in Kiss1r À/ÀR female mice, 122 suggesting that this effect was mediated by the kiss1r. Consistent with this finding, kisspeptin-234 was also found to block the kisspeptin-10-induced increase in prolactin release in OVX þ E2 rats.…”

“…Surprisingly, however, this antagonist did not alter the concurrent reduction in the activity of TIDA neurons seen after ICV kisspeptin treatment. 122 These data suggest that the kisspeptin-mediated suppression of TIDA neuronal activity is independent of kiss1r, and that there are perhaps more than one mechanism by which kisspeptin can regulate prolactin secretion (e.g., by stimulating a PRF).…”

“…Our findings demonstrated that Kiss1r is expressed in both the anteroventral periventricular nucleus (AVPV), periventricular nucleus of the hypothalamus (Pe), and arcuate nucleus but not in dopaminergic neurons, as demonstrated by the absence of coexpression with TH. 122 We have further investigated this question using whole-cell patch clamp recordings in juvenile male rats, and we found no direct effect of kisspeptin-10 on the electrical activity of TIDA neurons. Similarly, others have reported that only a few TIDA neurons express Kiss1r in the female rat, 126 suggesting that Kiss1r does not play a significant role in this neuronal population.…”

“…127 We detected mRNA for the neuropeptide FF receptor 1 (Npffr1) in the majority of periventricular dopaminergic neurons and in a small proportion of TIDA neurons in the arcuate nucleus. 122 Given the affinity of kisspeptin for Npffr1, 128 this receptor is a possible alternative pathway for the kisspeptin action on hypothalamic dopaminergic neurons, an interesting question that remains to be directly addressed in future studies. Taken together, these findings suggest that kisspeptin-Kiss1r signaling seems to stimulate prolactin secretion through the activation of nondopaminergic neurons.…”

“…lacked Kiss1r or express Npffr1 only in a low proportion of the cells (16.5%), 122 it seems possible that kisspeptin signaling may not be the major function of these projections. Although there is no answer to this question at the moment, perhaps the other KNDy peptides functionally interact to regulate TIDA neurons.…”