Gamma-aminobutyric acidA receptor agonist, muscimol, increases KiSS-1 gene expression in hypothalamic cell models

Abstract

Purpose: Accumulating evidence indicates that hypothalamic kisspeptin plays a pivotal role in the regulation of the hypothalamic–pituitary–gonadal (HPG) axis. In this study, the direct action of the gamma-aminobutyric acid (GABA)A receptor agonist on kisspeptin-expressing neuronal cells was examined. Methods: A hypothalamic cell model of rat hypothalamic cell line R8 (rHypoE8) cells and primary cultures of neuronal cells from fetal rat brains were stimulated with a potent and selective GABAA receptor agonist, muscimol, to determine the expression of the KiSS-1 gene. Results: Stimulation of the rHypoE8 cells with muscimol significantly increased the level of KiSS-1 messenger (m)RNA expression. The ability of muscimol to increase the level of KiSS-1 mRNA also was observed in the primary cultures of the neuronal cells from the fetal rat brains. The muscimol-induced increase in KiSS-1 mRNA expression was completely inhibited in the presence of the GABAA receptor antagonist. Although muscimol increased the expression of KiSS-1, the natural compound, GABA, failed to induce the expression of KiSS-1 in the rHypoE8 cells. Muscimol did not modulate gonadotropin-releasing hormone expression in either the rHypoE8 cells or the primary cultures of the fetal rat brains. Conclusions: This study's observations suggest that the activation of the GABAA receptor modulates the HPG axis by increasing kisspeptin expression in the hypothalamic neurons.