Kara I. Gabriel - US grants

The proposed research is designed to investigate the effects of early postnatal handling as an environmental manipulation which may attenuate the adverse behavioral and physiological consequences of prenatal ethanol exposure. This research will examine the possible mechanisms mediating the hormonal hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol (E) as well as the possible influence of postnatal handling on these mechanisms. In addition, experiments will investigate the correspondence between prenatal ethanol-induced alterations in behavior and HPA activity. Toward achievement of these aims, experiments will involve behavioral and hormonal assessments. Tasks involving behavioral inhibition (conditioned taste aversion) and spatial learning (Morris water maze) will explore further the learning and/or performance deficits previously demonstrated in E animals as well as investigate the correspondence between behavior and HPA activity. Functional manipulations of the hypothalamic-pituitary-adrenal (HPA) axis will examine possible mechanisms of the altered hormonal responsiveness to stress observed in E animals as well as explore the effects of handling on this HPA hyperresponsiveness. Lastly, experiments will investigate the effects of prenatal ethanol exposure and postnatal handling on activity of the HPA axis under basal conditions to determine if altered steady state activity contributed to HPA differences following stress.

The goal of this proposal is to investigate developmental differences in ethanol responsiveness and in the biological substrates that underlie ethanol's effects. Specifically, the proposed experiments will examine the role of GABA-A receptor activity in ethanol-induced changes in anxiety in adolescent and adult BALB/cByJ and C57BL/6J mice. Initial experiments will characterize the anxiety-reducing (i.e., anxiolytic) effects of acute ethanol exposure (0, 1, 2 or 3 g/kg) in adolescent and aduit mice on three tests of anxiety-like behavior, the elevated zero-maze, the light/dark choice test, and novel object exploration (i.e., cork gnawing). After examining the behavioral effects of the GABA-A receptor antagonist, picrotoxin (0, 0.75, or 2.5 mg/kg), on the above tests, the ability of picrotoxin to attenuate or block ethanol's anxiolytic effects in adolescent and adult mice will be determined. A second series of experiments will characterize the anxiety-increasing (i.e., anxiogenic) effects of ethanol withdrawal (0 or 4 g/kg) in adolescent and adult BALB/cByJ and C57BL/6J mice (following determination of blood ethanol clearance rates). Because drugs that enhance GABA-A receptor activity, such as benzodiazepines, have been shown to attenuate withdrawal-induced increases in anxiety in adults, we will examine the ability of the benzodiazepine, diazepam (0, 1 or 2 mg/kg) to attenuate the anxiogenic effects of ethanol withdrawal in adolescent and adult mice. These experiments will provide data on anxiety-like behavior and ethanol responsiveness in adolescent animals as well as determine if behavioral differences in adolescent animals are mediated by developmental alterations in GABA-A receptor activity. Comparisons of inbred strains will permit a preliminary examination into the manner in which genetic influences on ethanol responses vary over ontogeny. It is hoped that a better understanding of ethanol's effects in adolescence will aid in the development of more effective prevention strategies or treatment for human adolescents.