Decreasing GAD neonatally attenuates steroid-induced sexual differentiation of the rat brain

During development, exposure to gonadal steroids results in brain sexual di fferentiation. Postnatally, hypothalamic gamma-aminobutyric acid (GABA) lev els are almost double in males versus females. We hypothesized that increas ed GABA neonatally results in masculinization. Males, females, and androgen ized females were infused intrahypothalamically with antisense oligonucleot ides against glutamic acid decarboxylase (GAD) mRNA at birth to reduce GABA synthesis. GAD protein and GABA levels were reduced 24 hr later without ob vious toxic effects, as determined by histological examination. As adults, neonatally antisense-treated, androgenized females showed reduced intromiss ion-like behavior and lordosis quotients compared with vehicle and scramble d controls. Lordosis quotients were reduced about 50% in nonandrogenized fe males versus vehicle and scrambled controls. These data suggest that GABA i s involved in mediating brain sex differentiation and may act in both males and females.