ALCOHOL, GABA AND HORMONES: PHYSIOLOGY OF SUBUNIT CHANGE

点击翻译按钮获取中文摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) It is well known that pre-menstrual syndrome (PMS) is associated with increased ethanol consumption, which may then act to counteract premenstrual dysphoria. The purpose of this study is to examine changes in ethanol modulation of GABA function during P withdrawal, a rodent model of PMS, as a possible mechanism which may explain increased alcohol consumption during the pre-menstrual period. In addition, this paradigm will allow us to assess ethanol effects under conditions of GABA receptor subunit plasticity produced by physiologically relevant hormonal changes. For this model, animals are exposed in vivo to progesterone for three weeks and tested 24 hrs after cessation of treatment. Previous findings from this lab suggest that withdrawal from the GABA-modulatory 3aOH-5apregnan-20-one using this paradigm results in increased anxiety and seizure susceptibility due to decreases in total integrated GABA-gated current as a result of a markedly faster decay time constant for hippocampal pyramidal cells. This change in GABA current kinetics was due to significant increases in the a4 subunit of the GABA receptor. The goal of the present studies is to determine the effect of a4 subunit upregulation on ethanol effects on GABA-gated current and inhibitory synaptic currents recorded from the hippocampal slice preparation (mIPSCs and sIPSCs) correlated with a4 subunit levels using Western blot procedures. This study will test two potential mechanisms which may act to alleviate PMS-symptoms using acute and sustained ethanol treatment. It is our hypothesis that acute ethanol will increase peak GABA-gated current, while sustained ethanol administration will decrease levels of the a4 subunit in conjunction with return of GABA-gated current decay time to control levels following P withdrawal. Enhancement of GABA function by ethanol may then be reinforcing in an anxiolytic fashion to individuals suffering from PMS. Understanding the physiological changes involved in hormone-associated changes in alcohol effects may provide additional insight into potential mechanisms leading to alcohol abuse.