Our goals are to identify alterations in neurochemistry that occur in the extended amygdala following chronic alcohol administration and examine the hypothesis that endogenous K-opioid receptor (KOR) systems attenuate the neurochemical and behavioral effects of alcohol. We postulate that activation of KOR systems by alcohol is a key homeostatic mechanism that opposes the development of alcohol dependence, and that dysregulation of KOR systems results in altered vulnerability to the reinforcing effects of alcohol and to alcohol addiction. We will test these postulates pharmacologically in wild-type mice, and by using mice with constitutive deletion of the gene encoding the KOR-1 receptor or dynorphin, the endogenous KOR ligand.
Specific Aim 1 will characterize alterations in dopamine, GABA and glutamate neurotransmission that occur in the nucleus accumbens (Acb) and central nucleus of the amygdala during abstinence from chronic alcohol administration and determine whether hypofunction of KOR systems exacerbates these effects. The no net flux method of quantitative microdialysis will be used to monitor extracellular dopamine concentrations and changes in dopamine uptake and release. Conventional dialysis will be used to measure basal and stimulus (alcohol, KCI)- evoked dopamine, GABA and glutamate efflux.
Specific Aim 2 will determine whether hypofunction of KOR systems alters adaptations in behavior that occur following chronic alcohol administration. We will measure somatic signs of alcohol withdrawal and sensitization of the withdrawal response that occurs after repeated bouts of alcohol intoxication and withdrawal.
Specific Aim 3 will determine whether KOR system hypofunction results in increased sensitivity to the rewarding effects of ethanol and whether dopamine dynamics are altered in the Acb and amygdala of mice self-administering alcohol. Operant oral alcohol self- administration will be used to characterize the rewarding effects of alcohol and microdialysis will be used to monitor neurotransmitter dynamics in self-administering mice. The data derived from these studies will delineate neuroadaptations that occur in the extended amygdala following both context-dependent and independent alcohol administration and the role of endogenous opioid systems in modulating the neurochemical effects of alcohol, alcohol dependence, and reward.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA013486-05
Application #
6945465
Study Section
Special Emphasis Panel (ZAA1-DD (20))
Program Officer
Twombly, Dennis
Project Start
2001-09-27
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2005
Total Cost
$245,954
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
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
Job, Martin O; Tang, Amanda; Hall, F Scott et al. (2007) Mu (mu) opioid receptor regulation of ethanol-induced dopamine response in the ventral striatum: evidence of genotype specific sexual dimorphic epistasis. Biol Psychiatry 62:627-34
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
Chefer, Vladimir I; Zapata, Agustin; Shippenberg, Toni S et al. (2006) Quantitative no-net-flux microdialysis permits detection of increases and decreases in dopamine uptake in mouse nucleus accumbens. J Neurosci Methods 155:187-93
Zapata, Agustin; Shippenberg, Toni S (2006) Endogenous kappa opioid receptor systems modulate the responsiveness of mesoaccumbal dopamine neurons to ethanol. Alcohol Clin Exp Res 30:592-7
Zapata, Agustin; Gonzales, Rueben A; Shippenberg, Toni S (2006) Repeated ethanol intoxication induces behavioral sensitization in the absence of a sensitized accumbens dopamine response in C57BL/6J and DBA/2J mice. Neuropsychopharmacology 31:396-405
Margolis, Elyssa B; Lock, Hagar; Chefer, Vladimir I et al. (2006) Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci U S A 103:2938-42
Doyon, William M; Howard, Elaina C; Shippenberg, Toni S et al. (2006) Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration. Neuropharmacology 51:487-96
Hauser, Kurt F; Aldrich, Jane V; Anderson, Kevin J et al. (2005) Pathobiology of dynorphins in trauma and disease. Front Biosci 10:216-35
Gonzales, Rueben A; Job, Martin O; Doyon, William M (2004) The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement. Pharmacol Ther 103:121-46

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