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    • Introduction Substantial body of evidence supports the notio

    2022-01-05

    Introduction Substantial body of evidence supports the notion that GABA, the dominant inhibitory neurotransmitter in the hypothalamus of mammals, affects GnRH release by two classes of membrane receptors: GABAA (GABAAR) [1] and GABAB (GABAB R) [2]. Studies in rodents and sheep have documented that GnRH bwx express these receptor molecules [[3], [4], [5], [6]]. Furthermore, GABAergic synapses have also been identified on GnRH neurons [7,8]. GABA acting through GABAA and GABAB receptor mechanisms may stimulate [[9], [10], [11], [12]] or inhibit [[13], [14], [15]] activity of GnRH cells and GnRH/LH release depending on the animal's physiological state, experimental conditions, and site of its action. In vitro experiments in mice and rats have indicated that the activation of GABAAR depolarizes as well as hyperpolarizes GnRH cells [6,[16], [17], [18]]. Some studies have also suggested that GABA could excite [12,19,20] or inhibit [21] the firing rate of GnRH neurons. The GABAergic system may serve as a primary integrating center in the hypothalamus for many inputs to GnRH cells. It has been proven that signals from gonadal hormones [22,23] and many neuronal systems [22,24] alter GABAergic drive to GnRH neurons and ultimately affect the GnRH output. It is generally accepted that muscimol, a selective agonist of GABAAR, decreases GnRH/LH secretion in sheep [13,14,25]. The effects of GABAAR blocker, bicuculline, on GnRH/LH release have been variable and largely dependent upon physiological state of the animal, its sex and experimental conditions. In ovariectomized ewes, bicuculline suppressed LH release [13], but in follicular-phase animals it had no evident effect on the extracellular concentration of GnRH in (preoptic area) POA and (ventromedial hypothalamus) VMH [14]. The dialysis of bicuculline into POA of the castrated rams resulted in reduced LH release [26]. On the other hand, its infusion into the third cerebral ventricle of follicular-phase sheep stimulated LH secretion [25]. The mechanisms and mediators by which GABA affects hypothalamic-pituitary GnRH/LH system in sheep are not well recognized. However, it seems highly probable that GABA may involve interneurons that provide afferents to GnRH system [11], because as yet, there is no information in the subject literature about direct GABA action on GnRH/LH secretion in ewes. Identification of kisspeptin (Kiss 1) and its G protein-coupled receptor 54 (Kiss1r) as an essential component of the hypothalamic-pituitary-gonadal (HPG) axis controlling GnRH/LH release [27] raises the possibility that Kiss 1-Kiss1r signaling may play an essential role in the transduction of GABA-induced changes in GnRH/LH secretion. The interactions between GABA and kisspeptin neurons in the control of GnRH/LH release are not elucidated in sheep. However, studies in other species imply the existence of GABA-kisspeptin relationship, at least in some aspects of the hypothalamo-pituitary unit essential for reproduction [28,29]. Thus, one important issue for clarification of the potential role of GABA-kisspeptin interconnections in the regulation of hypothalamic-pituitary reproductive axis of sheep is to explain whether kisspeptin neurons participate in GABAAR-mediated control of GnRH/LH system. Limited data in rats have also shown that changes in GABAergic neurotransmission affect the expression of GnRH [[30], [31], [32]] and GnRH receptor (GnRHR) [33,34] genes. Based on our previous study on follicular-phase sheep, GABA is believed to inhibit the transcriptional activity of GnRH and GnRHR genes in the hypothalamus and GnRHR in the (anterior pituitary) AP. This effect of GABA is probably indirectly mediated via GABAA R in the hypothalamus [25], thus suggesting the significance of this receptor mechanism in the control of GnRH and GnRHR biosynthesis. To get more insight in the role of GABAergic system in molecular control of the hypothalamic-pituitary reproductive axis, we analyzed the effects of prolonged intermittent infusions of GABAAR agonist (muscimol) or antagonist (bicuculline) (1) on levels of post-translational products of genes encoding GnRH and GnRHR in the POA-hypothalamus and GnRHR in the AP, (2) on the expression of mRNAs encoding Kiss 1 and Kiss1r in the POA-hypothalamic tissue continuum. The level of LH in the blood was also determined as an indicator of pituitary gonadotrophs activity. These interferences were studied in follicular-phase sheep – the animal species that are considered to be a good model in experiments on the neuroendocrine mechanisms regulating the process of reproduction [5,10,11,25,27].