The objective of this new research project is to investigate whether cognition-enhancing agents are effective in reversing fetal ethanol-induced deficits in hippocampal synaptic plasticity and learning using a rat model of moderate prenatal ethanol exposure. Within the time and budgetary constraints of the R21 grant funding mechanism, we will limit this initial """"""""proof of concept"""""""" investigation to an assessment of the effects of a single cognition enhancing agent on the performance of fetal ethanol-exposed offspring in two behavioral paradigms sensitive to moderate prenatal ethanol exposure. Subsequently, we will examine the effects of this agent on two measures of hippocampal synaptic plasticity, the physiologic mechanisms thought to subserve learning, which are also sensitive to moderate prenatal ethanol exposure. The working hypothesis for this project is that the cognition-enhancing histamine H3 receptor antagonist ABT-239 will diminish fetal ethanol-induced learning deficits by enhancing hippocampal synaptic plasticity in fetal ethanol-exposed offspring. We will examine the effects of five different doses of ABT-239 on fetal ethanolinduced deficits in contextual fear-conditioned learning (Aim 1A) and spatial navigation deficits in the Morris Water Task (Aim 1B). Then, we will conduct dose-response studies of the effects of ABT-239 on fetal ethanolinduced deficits in long-term potentiation in vivo (Aim 2A) and activity-dependent potentiation of electrically evoked amino acid release (Aim 2B) in the dentate gyrus of dorsal hippocampal formation. Based on our hypothesis, we predict that ABT-239 will improve performance on the learning tasks in a manner that corresponds to improvements in one or both measures of hippocampal synaptic plasticity. The long-term objectives of this research program are to determine whether this experimental approach can provide the pharmacologic rationale for initiating clinical trials of such agents for treating cognitive deficits associated with FASD and whether this rodent model of moderate prenatal ethanol exposure has utility for assessing the therapeutic potential of a variety of cognition-enhancing agents. ? ? ? ?
| Varaschin, Rafael K; Rosenberg, Martina J; Hamilton, Derek A et al. (2014) Differential effects of the histamine H(3) receptor agonist methimepip on dentate granule cell excitability, paired-pulse plasticity and long-term potentiation in prenatal alcohol-exposed rats. Alcohol Clin Exp Res 38:1902-11 |
| Savage, Daniel D; Rosenberg, Martina J; Wolff, Christina R et al. (2010) Effects of a novel cognition-enhancing agent on fetal ethanol-induced learning deficits. Alcohol Clin Exp Res 34:1793-802 |
| Rosenberg, Martina J; Wolff, Christina R; El-Emawy, Ahmed et al. (2010) Effects of moderate drinking during pregnancy on placental gene expression. Alcohol 44:673-90 |
| Varaschin, Rafael K; Akers, Katherine G; Rosenberg, Martina J et al. (2010) Effects of the cognition-enhancing agent ABT-239 on fetal ethanol-induced deficits in dentate gyrus synaptic plasticity. J Pharmacol Exp Ther 334:191-8 |
