The action of alcohol on the central nervous system (CNS) is complex; it targets multiple regions in the CNS but its effects on neurons in the targeted regions are incompletely understood. Clearly, alcohol exerts profound influences on a number of neurotransmitter systems, notably by modulating (potentiating or attenuating) the function of the respective receptors. Prominent among the modulated receptors are those that mediate the synaptic actions of the conventional inhibitory and excitatory neurotransmitters, y-aminobutyric acid-A type (GABA ) receptor and the ionotropic glutamate receptors. This component of the Alcohol Research Center application proposes to examine the alcohol-induced modulation of these neuroreceptors, focusing on the principal neuron in the striatum, the medium spiny neuron. The striatum and the medium spiny neuron have been implicated in contributing to the myriad of behavioral effects of alcohol. In addition, GABA and glutamate converge on this population of neurons to control its excitability. We will investigate the cellular and molecular aspects of the interaction between acute and chronic alcohol exposure on the functional properties of GABA and the ionotropic glutamate receptors associated with the medium spiny neuron. Our general hypothesis is two-fold: (1) acute exposure to alcohol exerts differential effects on these receptors and these effects are distinct from those exerted by chronic exposure; (2) changes in the functional properties of the receptors following chronic alcohol exposure can be accounted for and predicted by changes in the pattern of expression of receptor subunits or subtypes.
Three specific aims are proposed which combine patch clamp electrophysiology and mRNA expression profiling in single neurons, neurochemistry and immunohistochemistry.
Specific Aim 1 will test the specific hypothesis that alcohol modifies the sensitivity of medium spiny neurons to GABA glutamate, and will establish the subunit profile for each receptor population.
Specific Aims 2 and 3 will focus on the consequence of chronic exposure to alcohol and test the hypotheses that chronic alcohol exposure leads to changes in the functional properties of GABA and ionotropic glutamate receptors (Specific Aim 2), concomitant with changes in the expression of receptor subunit mRNAs and proteins (specific Aim 3). Our investigation should reveal important insights into the modulation of neuroreceptor function and synaptic mechanisms by alcohol. It should also validate conceptual and strategic approaches for studying alcohol's influence on other neurotransmitter systems and/or CNS regions.
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