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    • In the present study administration of both muscimol and

    2022-01-14

    In the present study, administration of both muscimol and bicuculline also affected the biosynthesis of GnRHR. A significant decrease in GnRHR level in the POA, AH, VMH and SME following muscimol treatment as well as the opposite effect induced by bicuculline indicates that GnRHR gene expression is, as in the case of the ligand, under GABA inhibitory control. The neuroendocrine processes that lead to decreased GnRHR levels in the POA-hypothalamic structures of sheep in response to muscimol with concomitant decrease in GnRHR mRNA [25] in the POA-hypothalamus are unknown. However, it cannot be excluded that the subpopulations of GnRHR-expressing neurons in various parts of the hypothalamus belong to different neuronal systems and are innervated by different inhibitory and/or disinhibitory afferents which specifically act on GnRHR gene transcription and/or post-transcriptional steps of GnRHR biosynthetic pathway. Hence, the final effect of all these events on GnRH biosynthesis may be determined by the net results of the inhibition and/or disinhibition of all these afferents on GnRHR-expressing neurons. The precise role of hypothalamic GnRHR in the control of gonadotropin secretion is yet to be determined. The question remains as to what the regulatory function is for muscimol-induced changes in GnRHR levels in particular in POA-hypothalamic areas. Studies in rats [33,62,63] and sheep [64] provided some evidence to believe that GnRHR in the VMH may participate in the regulation of GnRH secretion from the axon terminals of GnRH neurons in the SME. According to this, the activation of GnRHR in VMH exerts an inhibitory effect on GnRH release. Our current data potentially eliminated a critical role for the VMH population of GnRHR in GABA-induced suppression of GnRH release. This possibility has also been eliminated when highest levels of hypothalamic GnRHR during the estrous MK2 inhibitor vs anestrous period were determined in sheep [51]. Since biosynthesis of GnRHR has not been switched down in the hypothalamus of follicular-phase ewes, it seems that GnRHRs in this structure are not critical for season-mediated control of GnRH release. However, the mechanisms of stress-induced suppression of GnRH release may involve an active GnRHR role in the VMH [64]. The physiological significance of GnRHR has been well recognized in the AP and muscimol-induced down-regulation of GnRHR amount in this gland is not surprising. Indeed, it is well documented in rats and sheep that small doses of GnRH applied in a physiological pulsatile manner into the pituitary gland have a stimulatory effect on GnRHR gene expression [65,66], GnRHR activity [67,68], biosynthesis of LHβ subunit [69,70] and LH secretion [45]. Hence, the decrease and increase in GnRHR level in the AP of muscimol- or bicuclline-treated ewes, respectively, results mainly from changes in the hypothalamic GnRH release. On the other hand, a decrease in the level of LH in peripheral blood after muscimol administration may be due to diminished GnRHR activity in the AP, as a consequence of low secretory activity of GnRH cells. In conclusion, the present study emphasizes the significance of GABAA R in controlling GnRH/LH secretion. It provides strong support for the assumption that GABAAR-mediated suppression of GnRH/LH release in the hypothalamic-pituitary unit of follicular-phase sheep occurs by inhibition of molecular processes governing the biosynthesis of GnRH and GnRHR in hypothalamus as well as GnRHR in the AP. Lack of changes in the expression of mRNAs encoding Kiss 1 and Kiss1r in the POA-hypothalamus of muscimol- and bicuculline- treated ewes potentially excludes the participation of Kiss1/Kiss1r signaling in GABAAR-mediated control of GnRH and GnRHR biosynthesis. However, further work is required to clarify this point and to precisely determine the mechanisms of GABA action on GnRH system activity. However, our data are still preliminary and need to be verified by further experiments in which the relationship between primary transcript and post-translational products of Kiss 1 and Kiss1r genes should first be determined.