MECHANISMS OF ADDICTION PATHOGENESIS

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The purpose of this component of the ARC is to investigate the role of GABAergic neurotransmission, including neurosteroid modulation, in the initiation and maintenance of ethanol self-administration in rats. There is increasing behavioral evidence that mesolimbic GABA systems are involved in voluntary ethanol self-administration. However, there is a significant gap in our knowledge of the molecular mechanisms in brain that underlie alcohol self-administration and preference. Since we have previously found evidence for alterations in GABAa receptor sensitivity and expression in cortex following prolonged ethanol consumption, we propose to investigate the GABAergic mechanisms involved in mesolimbic brain regions following prolonged ethanol self-administration. These studies will delineate the role of GABAa, receptor function and gene expression in the control of ethanol self-administration in the nucleus accumbens, ventral tegmental area, amygdala and prefrontal cortex. We also propose to elucidate the role of neurosteroid modulators in ethanol self-administration. We plan to determine if the initiation and/or maintenance of ethanol self-administration alters endogenous neurosteroid synthesis or metabolism and if direct neurosteriod administration to the lateral ventricle, or mesolimbic brain sites alters ethanol self- administration. Previous studies have demonstrated gender differences in ethanol self-administration in the rat that could be related to gender differences in neurosteroid levels. We have also found differential effects on cerebral cortical GABAa receptor alpha1 subunit expression in female versus male rats. We propose to determine whether gender modulate GABAa receptor function, expression or neurosteriod metabolism in the GABAergic mesolimbic circuitry during initiation or maintenance of voluntary ethanol consumption. Finally, the effects of alterations in GABAa receptor expression on ethanol self-administration will be measured using vector-mediated gene delivery. This component is designed to test the overall hypothesis that ethanol self-administration is influence by differences in GABAa receptor function and/or neurosteroid levels in the nuclear accumbens, amygdala, ventral tegmental area and prefrontal cortex. We predict that ethanol self- administration will alter GABAa receptor sensitivity and neurosteroid levels in the mesolimbic circuitry of brain. These alterations will, in turn, regulate ethanol self-administration and contribute to the development of ethanol addiction. We predict that gender related differences in these systems will correlate with neurosteroid modulation of GAMAa receptors. Using vector-mediated gene transfer, we expect to be able to manipulate ethanol self-administration behavior, showing promise for new therapeutic approaches to alcoholism. These studies will make significant contributions to our understanding of etiology and pathogenesis of alcoholism.