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. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, for example, the opioid peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opioid receptor antagonist, but its mechanism is not known in detail. Mu opioid receptors are anatomically located in the ventral tegmental area (VTA) and are thought to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opioid receptor subtypes has not been firmly established. Our preliminary studies show that mu opioid receptors are involved in the mechanism by which ethanol stimulates dopamine release in the shell of the nucleus accumbens in the Long-Evans rat. However, it is still unknown whether mu opioid receptors are involved in the stimulation of mesolimbic dopamine system before or during voluntary ethanol administration. We propose to determine the dose- dependent effects of naltrexone (non-selective opioid receptor antagonist) and beta-funaltrexamine (selective mu opioid receptor antagonist on accumbal dopamine during operant self-administration of ethanol (Aim 1). Finally, the mechanism of the stimulation of mesolimbic dopamine during operant self-administration may involve an increase in the firing rate of dopamine neurons in the ventral tegmental area, but this has not been measured in vivo. We propose to do this in Aim 2. Together, the proposed experiments will help elucidate the role of mu opioid receptors in the modulation of mesolimbic dopamine activity by ethanol 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 o 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
Research Project (R01)
Project #
2R01AA014874-06A1
Application #
8632454
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Cui, Changhai
Project Start
2004-08-12
Project End
2018-05-31
Budget Start
2014-06-05
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$241,749
Indirect Cost
$61,749
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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Theile, J W; Morikawa, H; Gonzales, R A et al. (2011) GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons. Neuroscience 172:94-103
Ramachandra, Vorani; Kang, Francis; Kim, Christine et al. (2011) The ? opioid receptor is not involved in ethanol-stimulated dopamine release in the ventral striatum of C57BL/6J mice. Alcohol Clin Exp Res 35:929-38
Morikawa, Hitoshi; Morrisett, Richard A (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235-88
Theile, Jonathan W; Morikawa, Hitoshi; Gonzales, Rueben A et al. (2009) Role of 5-hydroxytryptamine2C receptors in Ca2+-dependent ethanol potentiation of GABA release onto ventral tegmental area dopamine neurons. J Pharmacol Exp Ther 329:625-33
Theile, Jonathan W; Morikawa, Hitoshi; Gonzales, Reuben A et al. (2008) Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcohol Clin Exp Res 32:1040-8
Ramachandra, Vorani; Phuc, Steven; Franco, Ana Crystal et al. (2007) Ethanol preference is inversely correlated with ethanol-induced dopamine release in 2 substrains of C57BL/6 mice. Alcohol Clin Exp Res 31:1669-76
Job, Martin O; Ramachandra, Vorani; Anders, Sheneil et al. (2006) Reduced basal and ethanol stimulation of striatal extracellular dopamine concentrations in dopamine D2 receptor knockout mice. Synapse 60:158-64