The mechanisms that underlie the development and maintenance of ethanol self-administration are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. It is clear that ethanol administration stimulates dopamine release in this system, but the role of dopamine in ethanol self-administration behavior during various phases of exposure to ethanol is unclear. Previous studies funded by this grant show that dopamine activity undergoes plasticity during the earliest period of development of the reinforcing properties of ethanol. A transient increase in accumbal dopamine occurs during consumption of ethanol after a few days of exposure to ethanol, but not during an initial exposure. This transient increase in dopamine is correlated with exposure to the stimulus properties of ethanol rather than the brain concentration of ethanol. This suggests that the dopamine signal is playing a physiological role that predicts the rewarding effects of ethanol that will be experienced as the brain ethanol concentrations rise. Therefore, we hypothesize that the dopamine activity contributes to the development of the self-administration behavior. If so, inhibiting the dopamine signal with pharmacological antagonists in the nucleus accumbens should inhibit or retard the acquisition of ethanol self-administration behavior. We propose to test this in aim 1 by measuring the rate of acquisition of ethanol self-administration in the presence of selective antagonists of dopamine D1/D5, D2, and D3 receptors that will be microinjected into the nucleus accumbens. The second and third aims will focus on the potential mechanism for maintenance of ethanol self-administration behavior. Long term self- administration may lead to a habit-like intake of ethanol which may result from recruitment of neural circuits in the dorsal striatum.
Aim 2 will directly test the hypothesis that habitual intake of ethanol occurs after long term training. This will be done by using a devaluation procedure to produce an aversive state after ethanol administration, and then testing whether ethanol-seeking behavior is maintained under this new condition.
Aim 3 will test the hypothesis that dopamine in the dorsal striatum is released during ethanol consumption after the development of reliable ethanol self-administration.
Aim 4 will test the hypothesis that blockade of dopamine receptors in the dorsal striatum will inhibit habitual ethanol consumption. Together the experiments proposed will provide new data on the role of dopamine in the various stages of the development of ethanol reinforcement in a behaviorally relevant context.

Public Health Relevance

The proposed studies on alcohol drinking behavior are highly relevant to humans. A significant proportion of U.S. citizens suffer from the deleterious effects of excessive alcohol drinking, and this leads to tremendous suffering of their families as well as society. Therefore, understanding the effects of alcohol on basic brain function and behavior and the underlying mechanisms in a rat model can provide information about public policy, prevention, and medical interventions in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA011852-12
Application #
8305069
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2000-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$267,298
Indirect Cost
$86,496
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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
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
Shnitko, Tatiana A; Taylor, Sarah C; Stringfield, Sierra J et al. (2016) Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain. Psychopharmacology (Berl) 233:2045-54
Valenta, John P; Gonzales, Rueben A (2016) Chronic Intracerebroventricular Infusion of Monocyte Chemoattractant Protein-1 Leads to a Persistent Increase in Sweetened Ethanol Consumption During Operant Self-Administration But Does Not Influence Sucrose Consumption in Long-Evans Rats. Alcohol Clin Exp Res 40:187-95
Doherty, James M; Gonzales, Rueben A (2015) Lack of effect of nucleus accumbens dopamine D1 receptor blockade on consumption during the first two days of operant self-administration of sweetened ethanol in adult Long-Evans rats. Alcohol 49:543-51
Vena, Ashley A; Gonzales, Rueben A (2015) Temporal profiles dissociate regional extracellular ethanol versus dopamine concentrations. ACS Chem Neurosci 6:37-47
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
Doherty, James M; Gonzales, Rueben A (2015) Operant self-administration of sweetened ethanol and time course of blood ethanol levels in adolescent and adult male Long-Evans rats. Alcohol Clin Exp Res 39:485-95
Barker, Jacqueline M; Corbit, Laura H; Robinson, Donita L et al. (2015) Corticostriatal circuitry and habitual ethanol seeking. Alcohol 49:817-24
Mangieri, Regina A; Cofresí, Roberto U; Gonzales, Rueben A (2014) Ethanol exposure interacts with training conditions to influence behavioral adaptation to a negative instrumental contingency. Front Behav Neurosci 8:220

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