Evidence That Dopamine Acts via Kisspeptin to Hold GnRH Pulse Frequency in Check in Anestrous Ewes

Abstract

Recent work has implicated stimulatory kisspeptin neurons in the arcuate nucleus (ARC) as important for seasonal changes in reproductive function in sheep, but earlier studies support a role for inhibitory A15 dopaminergic (DA) neurons in the suppression of GnRH (and LH) pulse frequency in the nonbreeding (anestrous) season. Because A15 neurons project to the ARC, we performed three experiments to test the hypothesis that A15 neurons act via ARC kisspeptin neurons to inhibit LH in anestrus: 1) we used dual immunocytochemistry to determine whether these ARC neurons contain D2 dopamine receptor (D2-R), the receptor responsible for inhibition of LH in anestrus; 2) we tested the ability of local administration of sulpiride, a D2-R antagonist, into the ARC to increase LH secretion in anestrus; and 3) we determined whether an antagonist to the kisspeptin receptor could block the increase in LH secretion induced by sulpiride in anestrus. In experiment 1, 40% of this ARC neuronal subpopulation contained D2-R in breeding season ewes, but this increased to approximately 80% in anestrus. In experiment 2, local microinjection of the two highest doses (10 and 50 nmol) of sulpiride into the ARC significantly increased LH pulse frequency to levels 3 times that seen with vehicle injections. Finally, intracerebroventricular infusion of a kisspeptin receptor antagonist completely blocked the increase in LH pulse frequency induced by systemic administration of sulpiride to anestrous ewes. These results support the hypothesis that DA acts to inhibit GnRH (and LH) secretion in anestrus by suppressing the activity of ARC kisspeptin neurons.

The Effects of Chronic Subcutaneous Administration of an Investigational Kisspeptin Analog, TAK-683, on Gonadotropin-Releasing Hormone Pulse Generator Activity in Goats

“…Given that kisspeptin is involved in GnRH pulse generation [21,22,23,24] and chronic TAK-683 administration abrogates kisspeptin signaling-relating pulsatile GnRH/LH secretion, as discussed above, the present results, together with those of previous studies, propose several important aspects to the role of endogenous kisspeptin.…”

“…Moreover, the central administration of a kisspeptin antagonist blocks or attenuates pulsatile GnRH/luteinizing hormone (LH) secretion in monkeys and sheep [22,23,24]. These lines of evidence suggest that kisspeptin is greatly involved in the cascade driving pulsatile GnRH secretion, yet evidence for this proposal remains circumstantial.…”

The role of RFamide-related peptide 3 (RFRP3) in regulation of the neuroendocrine reproductive and growth axes of the boar

“…Characterizations of LH pulses were adapted from previously described factors (Goodman et al, 2012): (1) the peak occurred within two samples of the previous nadir, (2) pulse amplitude exceeded assay sensitivity, and (3) the peak was two standard deviations above the preceding nadir (nadir concentrations within animal). Luteinizing hormone pulse frequency was quantified across all periods.…”

Concentraciones de LH en periodos de transición reproductiva en cabras criollas x Nubia con diferente condición nutricional

“…Asimismo, el estrés nutricional también puede ocasionar un aumento en la sensibilidad del hipotálamo a la retroalimentación negativa de los estrógenos en rumiantes domésticos, lo cual afecta negativamente la secreción pulsátil de GnRH/LH y consecuentemente, la actividad cíclica ovulatoria (7,8) . Se considera que en estos animales el mediador del efecto de retroalimentación negativa de los estrógenos sobre la secreción de GnRH/LH, es un grupo neuronal localizado en la región mediobasal del hipotálamo que utiliza a las Kisspeptinas, Neurocinina B y Dinorfina como neuromediadores (neuronas KNDy) (9) . De acuerdo a lo anterior, es posible que en rumiantes domésticos estacionales, las neuronas KNDy actúen como integradoras de las señales fotoperiódicas y nutricionales para determinar la duración del periodo anovulatorio.…”

“…Nutritional stress can also cause an increase in the hypothalamic sensitivity to the negative feedback of estrogens in domestic ruminants, event which in turn negatively affects the pulsatile GnRH/LH secretion and consequently the cyclic ovulatory activity (7,8) . A neuronal group located in the mediobasal hypothalamus, that uses the Kisspeptines, Neurokinin B and Dynorphin as neurotransmitters (KNDy neurons), is considered to be the mediator of the negative feedback effect of estrogens on the GnRH/LH secretion in domestic ruminants (9) . In this way, it is possible that in seasonal domestic ruminants, KNDy neurons act as integrators of photo periodical and nutritional signals to determine the duration of the anovulatory period.…”