The shell nucleus accumbens (Nacc) comprises a critical component of the extended amygdala that receives a dopaminergic (DA) projection from the ventral tegmental area a glutamatergic (GLU) projection from the basolateral amygdala. Historically, the GABAergic projection neurons of the Nacc have been the focus of efforts to understand the alterations in neurochemical and synaptic structure and function that may underlie drug dependence and reinforcement phenomena. However, it is becoming increasingly apparent the cholinergic interneurons of the nucleus accumbens (CHI-NAccs) have experienced a relative dearth of analysis in drug abuse. This lack of analysis of these cells is especially disconcerting since it is apparent that these neurons are (1) critical neuronal integrators and modulators (2) possess key receptors and receptor-activated intracellular pathways important for plasticity and drug abuse, (3) express LTP and learning (4) exert powerful influences onto output projection neurons and (5) are compromised in clinical disorders such as schizophrenia, which can be induced by drug abuse. This accumulating evidence has led the P1 to hypothesize that these CHI-NAss may play a critical role in excessive ethanol consumption since these neurons share similar cellular, molecular and behavioral mechanisms with those involved in addiction for preliminary data examining the expression of immediate early genes (IEGs) in cholinergic interneurons following the self-administration of cocaine in rats). This project will test the hypothesis that ethanol induced neuroadaptation (i.e. changes in IEGs and receptors) and synaptic rewiring occurs on CHI-NAccs via """"""""Hebbian- like"""""""" associative convergence of the activity of VTA and amygdaloid afferents. The following 4 specific aims are designed as a comprehensive test of this hypothesis. We seek to characterized ethanol induced IEG expression, dynamic trafficking of key DA/GLU synaptic components and synaptic rewiring within shell nucleus accumbens cholinergic neuronal networks in animal models of excessive ethanol consumption. We will also seek to determine the alterations of key DA/GLU components in relation to ethanol mice genetic models and ethanol exposure. The findings from this work should contribute to a better understanding of the neuronal mechanisms that cause or predict excessive ethanol consumption and toward the development of improved behavioral and pharmacological prevention treatments for alcoholism and alcohol abuse.
