Sexually dimorphic influence of prenatal exposure to diazepam on behavioral responses to environmental challenge and on gamma-aminobutyric acid (GABA)-stimulated chloride uptake in the brain.

Early developmental exposure to diazepam (DZ) via administration of the drug to the pregnant rat (1.0 or 2.5 mg/kg) over gestational days 14 to 20 altered both behavior of adult progeny on two tests of anxiety and function of the benzodiazepine/gamma-aminobutyric acid (GABA) receptor complex (a neural substrate of anxiety-related behavior) in a sexually dimorphic manner. Adult male rats (60-90 days) exposed in utero to DZ spent significantly more time on the open arm of the elevated plus-maze than male rats exposed to vehicle, whereas plus-maze performance in female rats was unaffected by the early drug exposure. Similarly, early exposure to DZ markedly altered environment-specific social interaction in male rats, leading to increased social interaction in the unfamiliar environment and decreased social interaction in the familiar environment. Social interaction in adult female rats is not normally environment-specific; however, female rats exposed in utero to DZ at 2.5 mg/kg demonstrated a significant effect of the novel environment on social interaction, thus responding like unmanipulated male rats. The sensitivity of GABA-mediated 36chloride uptake to GABA was enhanced in synaptoneurosomes from male rats exposed in utero to DZ at 2.5 mg/kg and early exposure to either dose of DZ prevented the facilitative effect of DZ added in vitro on GABA-mediated chloride uptake. Function of the receptor complex was not altered in female rats by early DZ exposure. Thus, perinatal insults at the molecular level may underlie gender-related behavioral disorders in the young adult.