The neurochemical mechanisms which underlie ethanol self-administration behavior are not well understood at present. Recent research has suggested that brain systems which mediate reinforcement of behavior are probably involved in the development and promotion of ethanol self- administration. One of the major pathways thought to be involved in reinforcement is the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc). The goal of the present proposal is to test specific hypothesis about the involvement of dopamine in ethanol self-administration behavior in rats which have been trained to drink pharmacologically relevant amounts of ethanol. The major hypotheses to be tested are: (1) increased dopaminergic activity in the NAcc before or during ingestion underlies the control of ethanol and sucrose self-administration, (2) ethanol produces a different pattern of dopamine output in the NAcc compared with sucrose self- administration, (3) ethanol levels in brain produced by self- administration control, in part, dopamine levels in the NAcc along with the timing and pattern of subsequent ethanol drinking bouts, and (4) the mechanism for ethanol's effects on dopamine output is by increasing the release rather than inhibiting the uptake of dopamine. Five experiments will be carried out to determine (1) the relationship between extracellular dopamine in the NAcc during ethanol or sucrose self- administration in a limited access model, (2) the concentration-effect relationship between brain ethanol and extracellular dopamine during limited access self-administration, (3) if the change in dopamine during 6 hours of access to ethanol is the same as during 30 minute limited access to ethanol, (4) whether ethanol concentrations in brain are related to extracellular dopamine concentrations during 6 hour access to ethanol, and (5) if i.p. administered ethanol alters the in vivo recovery of dopamine or the true extracellular concentration using quantitative microdialysis methodology (point of no-net-flux). Together the results of these experiments will clarify the potential role of dopamine as a neurochemical mediator in the control of ethanol self- administration under conditions in which the ethanol is clearly reinforcing. In addition, the project will provide direct experimental support for the mechanism by which ethanol affects mesolimbic dopaminergic function in vivo. Increased understanding of the neurochemical mechanisms which underlie ethanol self-administration behavior may lead to new approaches for therapy of alcohol abuse and alcoholism.
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