A large number of pregnant women drink alcohol (ETOH) or take benzodiazepines (BZ). Although the effects of large doses of these drugs on the fetus are well studied, and the consequences of moderate ETOH consumption or therapeutic doses of BZ are not well described. With lower doses, behavioral teratology may be of greater importance than gross congenital anomalies. Hyperactivity and intellectual deficiencies are well-recognized characteristics of the fetal alcohol syndrome. Behavioral teratology of the BZ has not been studied in humans, however high dose studies in animals indicate impaired performance on a number of behavioral tests, developmental retardation, and learning impairment. The objective of this proposed research is to evaluate alterations in the neuropharmacology of the BZ-GABA-receptor ionophore complex following fetal exposure to ETOH, BZ, and the combination of the two. In the current proposal, we plan to study the fetal effects of maternal doses of BZ on the receptor-ionophore complex and on behavior in the offspring of CD-1 mice. We will examine the effects of low and moderate maternal ETOH administration on BZ receptor binding and behavior. Lastly, we will examine the interaction of maternal ETOH and BZ, a commonly encountered drug combination in humans, on the offspring of CD-1 mice. We have chosen to study the three BZ which are most commonly prescribed and abused - diazepam, alprazolam, and lorazepam. Specifically, we plan to assess binding characteristics of the BZ-receptor complex (binding in vivo and in vitro, picrotoxin-site binding, and muscimol-stimulated chloride uptake) in offspring of mice exposed during different periods of pregnancy or lactation to BZ, low and moderate dose ETOH, and a combination of BZ and ETOH. To evaluate differences in behavior (by means of open-field activity and elevated plus-maze measures) in maturing mice exposed during different periods of fetal and neonatal development to BZ, ETOH, and the combination and to characterize the time course and degree of motor impairment caused by BZ in the mature offspring of exposed mice, and compare these measures to concomitantly determined BZ binding characteristics. In addition we plan to evaluate any possible pharmacokinetic contributions to altered drug response in the mature offspring of exposed mice.
| Ciraulo, D A; Barnhill, J G; Ciraulo, A M et al. (1997) Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men: subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone. J Clin Pharmacol 37:64-73 |
