Gamma‐aminobutyric acid(A) receptor agonist, muscimol, increases KiSS‐1 gene expression in hypothalamic cell models

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 GABA(A) 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 GABA(A) 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 GABA(A) receptor modulates the HPG axis by increasing kisspeptin expression in the hypothalamic neurons.