Effect of N-methyl- d,l-aspartate (NMA) on gonadotropin-releasing hormone (GnRH) gene expression in male mice

Abstract

The glutamate analog N-methyl- d,l-aspartate (NMA) affects the regulation of GnRH and LH release in mammals. Several laboratories have reported a rapid and transient increase in GnRH mRNA levels of male rats after NMA injection. Studies employing the simultaneous measurements of nuclear GnRH primary transcript RNA, a reflection of gene transcription, and GnRH mRNA suggest that NMA’s effect on GnRH gene expression in the rat is likely due to post-transcriptional regulation. Despite the increasingly widespread use of transgenic mice, surprisingly little is known about the regulation of GnRH gene expression in the mouse. In this study, we assessed in detail the effects of NMA on GnRH gene expression in adult male mice. In the first experiment, GnRH mRNA levels in mice killed 60-min post-NMA injection (20 mg/kg bw, ip; n=9/treatment group) were lower ( P<0.05) when compared to controls (saline vehicle). In the second experiment, mice ( n=7/treatment group) were administered NMA or saline vehicle and were killed at 15-, 60- and 120-min post-injection. Consistent with the first experiment, treatment with NMA resulted in a significant decrease ( P<0.05) in cytoplasmic GnRH mRNA compared to control levels at 15- and 60-min but not 120-min. NMA treatment decreased the nuclear GnRH primary transcript RNA at 120-min but not at earlier time points. In summary, we have shown that regulation by NMA of GnRH gene expression in mice differs substantially from rats. This differential regulation of GnRH gene expression between rats and mice warrants further investigation.