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.
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.
|McGuier, Natalie S; Padula, Audrey E; Lopez, Marcelo F et al. (2015) Withdrawal from chronic intermittent alcohol exposure increases dendritic spine density in the lateral orbitofrontal cortex of mice. Alcohol 49:21-7|
|Lopez, Marcelo F; Laber, Kathy (2015) Impact of social isolation and enriched environment during adolescence on voluntary ethanol intake and anxiety in C57BL/6J mice. Physiol Behav 148:151-6|
|Griffin 3rd, William C (2014) Alcohol dependence and free-choice drinking in mice. Alcohol 48:287-93|
|Zhong, Zhi; Ramshesh, Venkat K; Rehman, Hasibur et al. (2014) Acute ethanol causes hepatic mitochondrial depolarization in mice: role of ethanol metabolism. PLoS One 9:e91308|
|Moorman, David E; Aston-Jones, Gary (2014) Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking. J Neurosci 34:10234-46|
|Anderson, Rachel I; Becker, Howard C; Adams, Benjamin L et al. (2014) Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models. Front Neurosci 8:33|
|Lopez, M F; Becker, H C; Chandler, L J (2014) Repeated episodes of chronic intermittent ethanol promote insensitivity to devaluation of the reinforcing effect of ethanol. Alcohol 48:639-45|
|Maldonado-Devincci, Antoniette M; Cook, Jason B; O'Buckley, Todd K et al. (2014) Chronic intermittent ethanol exposure and withdrawal alters (3?,5?)-3-hydroxy-pregnan-20-one immunostaining in cortical and limbic brain regions of C57BL/6J mice. Alcohol Clin Exp Res 38:2561-71|
|Becker, Howard C; Ron, Dorit (2014) Animal models of excessive alcohol consumption: recent advances and future challenges. Alcohol 48:205-8|
|Gass, Justin T; Glen Jr, William Bailey; McGonigal, Justin T et al. (2014) Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood. Neuropsychopharmacology 39:2570-83|
Showing the most recent 10 out of 87 publications