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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011852-03
Application #
6371481
Study Section
Special Emphasis Panel (ZRG1-ALTX-3 (01))
Program Officer
Egli, Mark
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$224,370
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Thakore, Neha; Reno, James M; Gonzales, Rueben A et al. (2016) Alcohol enhances unprovoked 22-28 kHz USVs and suppresses USV mean frequency in High Alcohol Drinking (HAD-1) male rats. Behav Brain Res 302:228-36
Vena, Ashley A; Mangieri, Regina; Gonzales, Rueben A (2016) Regional Analysis of the Pharmacological Effects of Acute Ethanol on Extracellular Striatal Dopamine Activity. Alcohol Clin Exp Res 40:2528-2536
Reno, James M; Thakore, Neha; Gonzales, Rueben et al. (2015) Alcohol-preferring P rats emit spontaneous 22-28 kHz ultrasonic vocalizations that are altered by acute and chronic alcohol experience. Alcohol Clin Exp Res 39:843-52
Barker, Jacqueline M; Corbit, Laura H; Robinson, Donita L et al. (2015) Corticostriatal circuitry and habitual ethanol seeking. Alcohol 49:817-24
Schier, Christina J; Dilly, Geoffrey A; Gonzales, Rueben A (2013) Intravenous ethanol increases extracellular dopamine in the medial prefrontal cortex of the Long-Evans rat. Alcohol Clin Exp Res 37:740-7
Valenta, John P; Job, Martin O; Mangieri, Regina A et al. (2013) ?-opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol. Psychopharmacology (Berl) 228:389-400
Schier, Christina J; Mangieri, Regina A; Dilly, Geoffrey A et al. (2012) Microdialysis of ethanol during operant ethanol self-administration and ethanol determination by gas chromatography. J Vis Exp :
Carrillo, Jennifer; Gonzales, Rueben A (2011) A single exposure to voluntary ethanol self-administration produces adaptations in ethanol consumption and accumbal dopamine signaling. Alcohol 45:559-66
Howard, Elaina C; Schier, Christina J; Wetzel, Jeremy S et al. (2009) The dopamine response in the nucleus accumbens core-shell border differs from that in the core and shell during operant ethanol self-administration. Alcohol Clin Exp Res 33:1355-65
Robinson, Donita L; Howard, Elaina C; McConnell, Scott et al. (2009) Disparity between tonic and phasic ethanol-induced dopamine increases in the nucleus accumbens of rats. Alcohol Clin Exp Res 33:1187-96

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