Intracellular Study of Ethanol Effects on Brain Neurons

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Dopaminergic (DA) neurons in the ventral tegmental area (VTA) provide the DA innervation of the nucleus accumbens and prefrontal cortex; this mesolimbic DA pathway is important for the rewarding properties of ethanol. Ethanol directly excites acutely dissociated DA VTA neurons in the absence of input from surround- ing cells. Ehanol excitation of DA VTA neurons is associated with a reduction in the action potential afterhyperpolarization (AHP) suggesting that it is due to a decrease in a potassium (K) current which contributes to the AHP. Ethanol excitation is completely blocked by quinidine, but not by the other K channel blockers. In whole cell voltage clamp experiments, ethanol reduced the sustained outward current. The overall objective of this project is to understand the cellular and molecular mechanism by which ethanol excites dopaminergic (DA) neurons of the ventral tegmental area (VTA), the cells of origin of the mesolimbic dopamine "reward" pathway. The goal of our studies is to understand the physiological basis of the rewarding effects of acute ethanol and how changes in the response of DA VTA neurons during chronic alcohol consumption lead to alcohol craving and addiction. We have identified KCNQ as one primary target for ethanol action of DA VTA neurons, but it is not the only potassium channel which is a target. In the Merit Extension period, we will test the following four Hypotheses: 1) The KCNQ channels of DA VTA neurons are sensitive to inhibition by ethanol. 2) Another fast-activating, delayed rectifier potassium channel also is sensitive to ethanol and plays a role in maintaining firing frequency. 3) Excitability of DA VTA neurons is reduced by ethanol, and this effect is separate from the effect of ethanol on firing frequency. 4) Ethanol- induced reduction in excitability is mediated by an effect of alcohol on the mechanism of the generation of spontaneous activity in DA VTA neurons. Once these hypotheses have been tested, the techniques and findings that have been generated can be applied in a number of ways, including correlating genetic differences in the identity of these membrane channels with drinking phenotypes, and determining whether chronic alcohol exposure results in specific changes in these ion channels and their response to alcohol. The results of these studies could have major implications for understanding differences in ethanol effects on the reward/reinforcement pathways of the brain related to alcoholism.