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.