ETHANOL/NEUROTRANSMITTER INTERACTIONS IN BRAIN NEURONS

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The overall objective of this project is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. Drugs acting on the serotonergic system reduce voluntary ethanol intake in laboratory animals and in clinical studies. These drugs may act at brain areas involved in reward to reduce alcohol craving. The ventral tegmental areas of Tsai (VTA) is important for mediating the rewarding properties of many drugs of abuse, including ethanol. Whole cell patch recording from acutely dissociated dopaminergic VTA neurons will be used to assess the action of ethanol and serotonin on these cells. Drugs will be applied in known concentrations. Ethanol causes excitation of most VTA neurons in extracellular and intracellular studies. We have shown that serotonin potentiates the excitatory effect of ethanol on VTA neurons, and this effect is mediated by 5-HT/2 receptors. We will investigate changes in specific membrane currents which may underlies serotonin potentiation of ethanol effects. Specific Aim #1 is to investigate the effects of serotonin and ethanol on potassium currents which mediate the after hyperpolarization following spontaneous action potentials. The specific currents which we intend to examine include two calcium-dependent potassium conductances, SK and BK, A-current (I/A), and the delayed rectifier. Specific Aim #2 is to determine how M-current, which is reduced by serotonin in other preparations, is affected by ethanol, serotonin and by the combination of ethanol and serotonin, in VT neurons. Specific Aim #3 is to determine whether serotonin alters h-current (I/h), a hyperpolarization-activated inward rectifier current, and to determine whether the effect of ethanol to enhance I/h is increased in the presence of serotonin. From the results of these experiments, a model will be developed to describe the interactions between the effects of serotonin and ethanol which result in potentiation of ethanol-induced excitation. These studies should elucidate the ionic mechanisms by which serotonin alters the action of ethanol in the VTA. This knowledge could be exploited to develop drugs for the treatment of alcoholism which reduce ethanol craving.