Phosphorylation and the CNS Actions of Ethanol

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The long-term goal of our research is to test the hypothesis that post-translational modifications such as phosphorylation are major contributors to brain region-specific responses to alcohol exposure. In the first round of funding we found that the sensitivity of the N-methyl-D-Aspartate receptor (NMDAR) to ethanol in specific brain regions is determined by the activation state of the non-receptor tyrosine kinases Fyn (activation) and Src (inhibition), leading to changes in the phosphorylation state of the NR2B (Fyn) and NR2A (Src) subunits of the NMDAR. We found that these signaling alterations lead to profound changes in the activity of the NMDAR during and after acute exposure to ethanol in slice preparations and in vivo. More recently, we identified an important role for Fyn and NR2B-NMDAR in the dorsal striatum in the long-lasting facilitation of NR2B-containing NMDAR-mediated activity after ethanol exposure and in ethanol drinking behavior. The NMDAR is an important mediator of ethanol's actions in the brain, and our results suggest that changes in the activation state of the Fyn in the dorsal striatum contribute to aberrant synaptic plasticity that may underlie the development of behavioral phenotypes such as the propensity to consume ethanol. Using molecular, biochemical, electrophysiological and behavioral approaches, we propose to elucidate the mechanism leading to, and are the consequences of, ethanol-mediated Fyn activation in the dorsal striatum of rats. As Fyn activity is both positively and negatively regulated by phosphorylation, we will determine the contribution of the tyrosine phosphatases, PTPalpha and STEP, to ethanol's actions on Fyn activation, NR2B phosphorylation and long-term facilitation of NMDAR activity in vivo. Additionally, we plan to investigate possible physiological consequences of dorsal striatal activation of Fyn. Finally, we will determine the contribution of Fyn, PTPalpha, and STEP to operant ethanol self-administration in rats. Our long-term goal is to understand the molecular mechanisms that contribute to the development of disease states associated with alcohol addiction. Identification of new intracellular targets that are mediators of alcohol addiction is an essential future direction for the development of novel interventions for alcohol related disorders.