Recently, individual differences that might predict risk for development of dependence and/or risk for relapse have been identified and are being investigated. Of interest to this component are individual differences in "trait-impulsivity." Findings in animals and humans suggest that a dysfunctional brain dopamine system underlies impulsive traits. Given that the brain dopamine system underlies both impulsivity and reward areas in the brain, it is not surprising that individuals high in trait-impulsivity show different brain regional activity to reward than individuals low in trait-impulsivity. Interestingly, these areas of activation are similar to what has been observed in non-treatment seeking alcoholics (NTSA) following presentation of alcohol cues. We found that aripiprazole, a partial dopamine receptor agonist that putatively "stabilizes" the dopamine system, reduces drinking and blocks alcohol cue-induced ventral striatal activity in NTSAs, and it does so most clearly in individuals with high trait-impulsivity.
The aim of the current proposal is to replicate and extend this original finding with aripiprazole, in a 2 medication group x 2 trait-impulsivity group prospective experimental design. In addition to studying the interaction of aripiprazole and trait-impulsivity, we also intend to systematically evaluate the role of trait-impulsivity and aripiprazole, per se, as main effects on drinking and craving using our well-validated, natural drinking, brain imaging, and bar-lab alcohol consumption paradigm. Finally, we intend to explore whether functional genetic variants in the brain dopamine system might underlie trait-impulsivity effects and/or aripiprazole response. We will screen about 120 NTSAs and randomize 100 to receive aripiprazole (N=50) (up to 15mg) or matching placebo (N=50) for 8 days. Barratt Impulsiveness Scale (BIS) scores will be used to divide the groups into low versus high trait impulsivity and will be an urn variable to insure equal distribution into both medication groups. After 6-days of natural drinking observation, all subjects will undergo an alcohol cue-induced brain activation (fMRI) paradigm (day-7) and the next day (day-8) will participate in a drinking bar-lab experiment. On day-9, subjects will receive educational counseling about heavy drinking and receive payment for participation.

Public Health Relevance

The ultimate goal of this work is to identify whether a subgroup of alcohol-dependent individuals might respond to aripiprazole. If this human laboratory study indicates that aripiprazole decreases cue-induced brain activation in the ventral striatum and reduces voluntary drinking, a clinical trial of aripiprazole in impulsive treatment-seeking alcoholics would be warranted. This work is very relevant to the goal of improving treatment for alcoholism by matching specific individuals to efficacious medication treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA010761-19
Application #
8601280
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
19
Fiscal Year
2014
Total Cost
$208,599
Indirect Cost
$62,328
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Rose, Jamie H; Karkhanis, Anushree N; Chen, Rong et al. (2016) Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens. Int J Neuropsychopharmacol 19:
Glover, Elizabeth J; McDougle, Molly J; Siegel, Griffin S et al. (2016) Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol. Alcohol Clin Exp Res 40:1651-61
Barker, Jacqueline M; Lench, Daniel H; Chandler, L Judson (2016) Reversal of alcohol dependence-induced deficits in cue-guided behavior via mGluR2/3 signaling in mice. Psychopharmacology (Berl) 233:235-42
Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary et al. (2016) The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res 1636:74-80
Uys, Joachim D; McGuier, Natalie S; Gass, Justin T et al. (2016) Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines. Addict Biol 21:560-74
den Hartog, Carolina; Zamudio-Bulcock, Paula; Nimitvilai, Sudarat et al. (2016) Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice. Neuropharmacology 107:451-9
Boyd, Stephen J; Schacht, Joseph P; Prisciandaro, James J et al. (2016) Alcohol-Induced Stimulation Mediates the Effect of a GABRA2 SNP on Alcohol Self-Administrated among Alcohol-Dependent Individuals. Alcohol Alcohol 51:549-54
Lopez, Marcelo F; Anderson, Rachel I; Becker, Howard C (2016) Effect of different stressors on voluntary ethanol intake in ethanol-dependent and nondependent C57BL/6J mice. Alcohol 51:17-23
Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2016) Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol. Neuropsychopharmacology 41:1112-27
Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2016) Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. Eur J Neurosci 43:710-20

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