INHIBITORY EFFECT OF 5-BETA-PREGNAN-3-ALPHA-OL-20-ONE ON GONADOTROPIN-RELEASING-HORMONE GENE-EXPRESSION IN THE MALE-RAT

Neuroanatomical data have documented the existence of synaptic contact s between gamma-aminobutyric acid (GABA) terminals and preoptic gonado tropin-releasing hormone (GnRH) neurons in the rat anterior hypothalam us. In addition, pharmacological studies have suggested that the GABAe rgic system may be involved in the control of gonadotropin release. Mo reover, it has been shown that some progesterone metabolites such as 5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha P) are able to interac t with the GABA(A), receptor complex. In the present study, we have in vestigated the effects of chronic (5 days) treatment with the GABA(A)- positive ligand 5 beta 3 alpha P (20 mg/kg body weight i.p., twice a d ay) or with the GABA(A) agonist muscimol (1 mg/kg body weight i.p., tw ice a day) alone or in combination on GnRH mRNA levels in the preoptic area of the male anterior hypothalamus as measured by in situ hybridi zation. Treatment with 5 beta 3 alpha P produced a 30% decrease in the number of grains overlying labelled cells, while muscimol treatment d ecreased the hybridization signal by 36%. The concomitant administrati on of 5 beta 3 alpha P and muscimol resulted in a 46% decrease in the GnRH mRNA levels. This inhibitory effect was completely antagonized by the concomitant administration of picrotoxin (4 mg/kg body weight i.p ., twice a day). These data suggest that the GABA(A) receptor complex and steroids that interact positively with this GABA(A) receptor compl ex may play an important role in the regulation of GnRH biosynthesis b y hypothalamic neurons.