Neuropharmacological Subsrates of Alcohol Addiction

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Recently we have demonstrated that a homogeneous population of gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) undergo adaptation in association with ethanol dependence. The overall objective of this proposal is to evaluate the role, whether contributory or reflective, of VTA GABA neurons in mediating the reinforcing properties of ethanol, under non-dependent and dependent conditions. The core thesis underlying this proposal is that adaptive changes in VTA GABA neuron excitability result from repeated exposure to acute intoxicating levels of ethanol and contribute to the dysregulation of mesolimbic dopamine homeostasis that accompanies ethanol reinforcement. Our proposed studies are designed to test three major hypotheses: 1) That persistent alterations in VTA GABA neuron excitability, N-methyl-D-aspartate (NMDA) and/or GABA receptor-mediated neurotransmission occur in association with ethanol dependence; 2) That enhancement of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission anticipates ethanol self-administration (SA); and 3) That adaptation of VTA GABA neuron excitability, NMDA and/or GABA neurotransmission parallels the continuum of ethanol intoxication, aversion, reinforcement and dependence. We will employ electrophysiological methods to determine if VTA GABA neuron firing rate, axonal excitability and/or NMDA and GABA receptor- mediated synaptic input undergo adaptation to chronic ethanol. We will evaluate VTA GABA neuron firing rate, axonal excitability and response to afferent synaptic input during ethanol self- administration and in the ethanol operant runway paradigms. These studies will determine if VTA GABA neurons or their corticolimbic inputs undergo plasticity during ethanol reinforcement. VTA GABA neurons may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction.