Sex-specific effects of chronic anabolic androgenic steroid treatment on GABAA receptor expression and function in adolescent mice

Anabolic androgenic steroids are synthetic derivatives of testosterone designed for therapeutic uses, but now taken as drugs of abuse. Potential health risks associated with anabolic androgenic steroid abuse are believed to be higher in adolescents than in adults, but few studies have tested anabolic androgenic steroid effects in adolescent subjects or determined if effects of these steroids differ between females and males. We have studied GABAA receptor expression and function in the medial preoptic nucleus of mice chronically treated during adolescence with the anabolic androgenic steroid, 17α-methyltestosterone. Three-week treatment did not elicit significant differences the expression of α1, α2 or α5 subunit mRNAs in animals of either sex, although there was a trend toward decreases in all three subunit mRNAs in female mice, which was augmented and attained significance for the α2 subunit mRNA in females treated for six weeks. Immunocytochemical analysis revealed that treatment with 17α-methyltestosterone for 6 weeks also elicited a significant decrease in the number of α2-immunopositive neurons in female subjects. To test if anabolic androgenic steroid treatment also promoted changes in GABAA receptor function, spontaneous inhibitory synaptic currents were analyzed in adolescent animals treated for 3-4 weeks. This treatment regimen promoted a significant decrease in spontaneous inhibitory synaptic current frequency in female, but not male mice. Finally, anabolic androgenic steroid treatment was found to have no effect on the numbers of interneurons within the medial preoptic nucleus, as assessed by immunoreactivity for calcium binding proteins, suggesting that the decrease in the frequency of spontaneous inhibitory synaptic currents in female mice does not arise from an anabolic androgenic steroid-induced loss of interneurons. Taken together, our results indicate that chronic exposure to 17α-methyltestosterone elicits significant changes in GABAergic transmission in the medial preoptic nucleus of female, but not male, mice effectively enhancing the sexually dimorphic nature of GABAergic transmission in a forebrain region crucial for the expression of aggression and sexual behaviors.