CELLULAR/MOLECULAR MECHANISMS UNDERLYING NEUROADAPTATION TO CHRONIC ALCOHOL

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These continuing studies of alcohol's actions on CNS neurons will determine if chronic exposure to alcohol produces long-lasting adaptive changes in cellular pathways involved in excitatory synaptic transmission. Alcohol's effects on synaptic functions that are critical to intracellular and interneuronal communication will be examined including: (a) intracellular Ca2+ signaling initiated by synaptic input, (b) neurosteroid modulation of synaptic transmission and long-term potentiation (LTP), and (c) transmitter interactions. These synaptic functions will be assessed under three conditions: (a) control baseline, (b) after chronic alcohol exposure and, (c) after a period of alcohol abstinence. A comparison of results will reveal alcohol-induced alterations in these synaptic functions and the relative permanence of the changes. Various strategies will be used to identify the cellular sites and mechanisms of alcohol action. The main transmitter to be studied is glutamate, and its actions via the NMDA receptor. Alcohol's action on opiate receptor-linked Ca2+ signaling will also be assessed. Neurons from two brain regions, the hippocampus and amygdala, will be studied. Both brain regions are known to be involved in the behavioral effects of alcohol. The Specific Aims of the studies are: (1) to investigate effects of chronic alcohol on intracellular Ca2+ signaling events activated by synaptic input and linked to glutamate and opiate receptors, and to determine if chronic alcohol induces long-term changes in receptor-linked Ca2+ signaling pathways that are maintained during abstinence from school. (2) To determine if neurosteroid modulation of excitatory synaptic transmission and LTP is altered by alcohol treatment paradigms that produce dependence and abstinence in animal models. (3) To establish a rodent culture model of amygdala neurons for studies of alcohol's effects on synaptic systems thought to be directly involved in addictive behavior. In vitro culture and slice preparations will be used for these studies because they offer technical advantages for the electrophysiological and microscopic Ca2+ imaging techniques to be used. Results from these studies will contribute significantly to an understanding of the neuroadaptive changes induced by alcohol under conditions of alcohol dependence and abstinence, and may reveal general principles that will contribute to an understanding of the basic neuronal mechanisms underlying alcohol's actions being studied in other components of the TSRI-ARC.