Prenatal diazepam exposure in rats: long-lasting, receptor-mediated effects on hypothalamic norepinephrine-containing neurons

The concentration and turnover of catecholamines (CAs) were measured in the cortex, hippocampus, and hypothalamus of rats exposed in utero to diazepam (DZ, 1.0, 2.5, or 10.0 mg/kg/day) over gestational days 13-20. Prenatal DZ induced a regionally specific, dose-related decrease in the level of norepinephrine (NE) (maximum decrease, 65%) and turnover rate of NE (maximum decrease, 85%) in the hypothalamus of 90-day-old adult rats. Dopamine levels were not altered in this region and neither of the CAs were altered in the other regions. Dividing the prenatal exposure period into two shorter periods revealed that late gestation (days 17-20) was the period when factors influencing NE function in the hypothalamus were most sensitive to DZ. Analysis of the development of the CA in the hypothalamus demonstrated that the effect of the prenatal exposure on NE levels did not become apparent until after 28 days of age. However, at 28 days, there was a dose-related increase in turnover rate of NE (maximum increase, 52%). Concurrent administration of the specific benzodiazepine (BZ) antagonist RO15-1788 with DZ (2.5 mg/kg) to pregnant rats effectively reversed the effects of DZ in the hypothalamus of the adult offspring, suggesting that the effects were mediated via the BZ receptor. These data have provided insight into the intricate processes of neuronal development; in particular the importance of target cell-nerve terminal interactions and the role of early developing receptors.