Cetrorelix, a Gonadotropin-Releasing Hormone Antagonist, Induces the Expression of Melatonin Receptor 1a in the Gonadotropin-Releasing Hormone Neuronal Cell Line GT1–7

Melatonin has been implicated in the control of the reproductive system, and the modulatory actions of melatonin on gonadotropin-releasing hormone (GnRH) neurons have been assumed to be indirectly mediated through afferent neurons. However, our previous studies demonstrate sexually dimorphic modulation of A-type γ-aminobutyric acid (GABA) receptor (GABAAR) currents by melatonin in adult rat GnRH neurons and a preferential expression of melatonin 1a receptor (MT1) in male GnRH neurons. Using immortalized GnRH neurons (GT1–7 cells), the present study investigated the mechanism by which the expression of melatonin receptors is regulated in GnRH neurons. Like endogenous GnRH neurons, GT1–7 cells express both GnRH and GnRH receptor mRNAs, indicating that the cells have a self-stimulatory system. A 2-iodomelatonin binding assay and RT-PCR analysis demonstrated that the cells expressed neither MT1 nor MT2. However, treatment of GT1–7 cells with the GnRH antagonist cetrorelix significantly increased 2-iodomelatonin binding and induced a time- and concentration-dependent MT1 mRNA expression. The GABAAR currents were then measured using a perforated patch-clamp technique to examine whether the treatment with cetrorelix changed the responses to melatonin. Melatonin augmented the GABAAR currents in GT1–7 cells treated with 1 μM cetrorelix for 24 h, while melatonin decreased the currents in the cells not treated with cetrorelix, probably via receptor-independent processes. The present results suggest that GnRH downregulates the expression of MT1 via an autocrine-paracrine mechanism in GT1–7 cells, and modifies the melatonin-induced modulation of GABAAR currents. These findings may provide one possible mechanism for the sexually dimorphic responses to melatonin in adult rat GnRH neurons.