Two major findings in the previous funding period will be pursued in the proposed 5-year extension period. First, we showed that a single experience with operant self-administration of ethanol produces a robust dopamine response on the second day of ethanol consumption, but not the first, and this accompanies an increase in ethanol consumption.
Aim 1 will test the hypothesis that it is the central effects of ethanol that the rats experience that leads to the behavioral and neurochemical changes. This will be done by limiting a group of rats so that they self-administer a dose of ethanol <0.25 g/kg. In addition, we propose to further characterize the time course of persistence of the behavioral and neurochemical response to a single exposure to operant ethanol self-administration. We predict that both the consumption and accumbal dopamine response will decay in a parallel manner which would be consistent with our interpretation that the dopamine response is part of a reward prediction system in the brain. A final part of this aim will be to do tract tracing to try to discover an anatomical basis for the subregional specificity of the dopamine response during consumption.
Aim 2 will focus on the prefrontal cortex and orbitofrontal cortex. Previous work indicated that the dopamine increases in the prefrontal cortex in rats that had been trained for one week to operantly self-administer sucrose or sucrose/ethanol solutions. We now propose to examine whether these responses In the prefrontal cortex develop after a single exposure to ethanol or sucrose. Furthermore we propose to extend the studies to measure norepinephrine in cortical dialysates, another important monoamine in the cortex. Also, we plan to study the orbitofrontal cortex, an area involved in decision making that has recently been found to be affected by ethanol.
Aim 3 will be a new direction, i.e., examination of the role of a neuroimmune factor, MCP-1, in ethanol self-administration. Both the agonist and antagonist will be infused into the ventricles and the acquisition of operant self-administration will be measured as well as the escalation of drinking after induction of physical dependence using a vapor chamber model.

Public Health Relevance

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 #
4R37AA011852-14
Application #
8653699
Study Section
Special Emphasis Panel (NSS)
Program Officer
Grakalic, Ivana
Project Start
1999-04-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
$277,497
Indirect Cost
$79,897
Name
University of Texas Austin
Department
Type
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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