Benzodiazepines are the most frequently prescribed psychotropic medications in the U.S., and are also among the most commonly abused classes of drugs.. Thus, prenatal exposure to benzodiazepines represents a potentially important clinical problem. Current data indicate that benzodiazepine use in pregnancy is substantial, and the recent description of benzodiazepine-induced embryopathy indicates potential serious effects. Animal studies in several species corroborate this clinical experience: offspring of benzodiazepines-exposed mothers exhibit behavioral alterations as newborns, in some cases persisting into maturity. Most behavioral studies addressed a limited range of parameters and little information is available concerning neurochemical effects of prenatal benzodiazepine exposure, in particular effects at the GABAa receptor complex. This proposal is designed to assess the behavioral and neurochemical effects of prenatal benzodiazepine exposure, utilizing the combined expertise of the co-investigators in behavioral, pharmacokinetic, and neurochemical studies. Preliminary data in a mouse model indicate behavioral alterations in prenatally exposed animals and alterations at the GABAa receptor. lie propose to extend these studies with lorazepam, a to classical"""""""" benzodiazepine, and alprazolam, a newer compound with possible unique effects. In mice, behavior and detailed neurochemical studies will be assessed across a broad range of the lifespan of the animal. Appropriate controls for drug delivery, nutrition, and fostering will be included. Neurochemical studies will include assessment of GABAa receptor mRNA. In primary neuronal tissue culture,neurochemical effects of alprazolam and lorazepam will be evaluated after various treatment intervals. In summary, experiments in mice will combine detailed behavioral and neurochemical assessments across a range of the animal lifespan, with appropriate controls. In tissue culture, neurochemical effects will be evaluated under controlled conditions.
