The neurochemical and cellular mechanisms that contribute to the control of ethanol drinking behavior 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, e.g., the opiate peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opiate receptor antagonist, but its mechanism is not known in detail. Mu opiate receptors are anatomically located in the ventral tegmental area (VTA) and are known 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 opiate receptor subtypes has not been firmly established. Our preliminary studies show that mu opiate receptors are involved in the mechanism by which ethanol stimulates dopamine release in the ventral striatum, one of the terminal areas of the mesolimbic system. We propose to determine whether genetic deletion or irreversible blockade of the mu opiate receptor alters the dose-response curve for ethanol-stimulated dopamine release in the ventral striatum (aim 1). The genetic model we propose to use will be congenic mu receptor knockouts and wild-type controls that have been established on a C57BL/6 background. These studies will be complemented by investigation of effects of irreversible blockade of mu receptors with the use of naloxonazine. We also will determine whether the deletion of the mu receptor or irreversible blockade alters ethanol consumption using a two bottle choice procedure (aim 2). Moreover, we propose to determine whether mu receptors in the ventral tegmental area or the ventral striatum are involved in the inhibitory effects of loss of mu receptor function on ethanol stimulated dopamine release (aim 3). This will be done by microinjection of naloxonazine into either area and measuring the ethanol response. The role of mu receptors in the control of VTA-dopamine neurons will be examined using electrophysiological measures of cellular and synaptic activity in GABAergic interneurons (aim 4). These studies will utilize both the genetic and pharmacological approaches as described above. Together, the proposed experiments will elucidate the role of mu opiate receptors in the modulation of mesolimbic dopamine activity by ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA014874-01
Application #
6758229
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
2004-08-12
Project End
2009-07-31
Budget Start
2004-08-12
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$323,550
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Zandy, Shannon L; Gonzales, Rueben A (2018) GABA Uptake Inhibition Reduces In Vivo Extraction Fraction in the Ventral Tegmental Area of Long Evans Rats Measured by Quantitative Microdialysis Under Transient Conditions. Neurochem Res 43:306-315
Cofresí, Roberto U; Lee, Hongjoo J; Monfils, Marie-H et al. (2018) Characterizing conditioned reactivity to sequential alcohol-predictive cues in well-trained rats. Alcohol 69:41-49
Zandy, Shannon L; Doherty, James M; Wibisono, Nathan D et al. (2017) High sensitivity HPLC method for analysis of in vivo extracellular GABA using optimized fluorescence parameters for o-phthalaldehyde (OPA)/sulfite derivatives. J Chromatogr B Analyt Technol Biomed Life Sci 1055-1056:1-7
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) 233:2045-2054
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
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
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
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

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