Neuropharmacological substrates of alcohol addiction

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DESCRIPTION (provided by applicant): We have identified a homogeneous population of y-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) that undergo adaptation in association with ethanol dependence. We have recently reported that VTA GABA neurons form part of a larger electrical network of ventral brain GABA neurons linked by connexin-36 gap junctions whose electrical coupling is enhanced by dopamine via D2 receptor-mediated activation of adenylate cyclase, and sensitive to low-dose ethanol. We hypothesize that VTA GABA neurons, and the electrical network they form, may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction. The overall objective of this application is to extend our evaluation of the role of this specific class of mesocorticolimbic GABA neurons in mediating the intoxicating and rewarding properties of ethanol. The core thesis underlying this proposal is that VTA GABA neurons underlie ethanol self-administration and that adaptive changes in VTA GABA neuron excitability and electrical synaptic transmission result from repeated exposure to contingent and/or non-contingent ethanol and contribute to the dysregulation of mesolimbic homeostasis that accompanies alcohol addiction. Our proposed in vivo and in vitro studies are designed to test four major hypotheses: 1) That VTA GABA neuron activity correlates with ethanol self-administration; 2) That lesioning VTA GABA neurons disrupts ethanol self-administration; 3) That gap junction transmission between VTA GABA neurons, or glutamate (GLU), GABA, or DA synaptic modulation of VTA GABA neuron gap junctions, is sensitive to ethanol; and 4) That persistent alterations in the gene expression of NMD A, non-NMDA, GABA, DA receptors, or connexin-36 gap junction proteins parallels the plasticity in synaptic adaptation that underlies the physiological manifestations of alcohol reward and dependence.