Alcoholism is a disorder characterized by a loss of control over drinking and relapse. While the rewarding effects of alcohol are essential for some aspects of drinking, recent findings suggest that heavy drinking is a maladaptive, persistent habit involving a transition from decision-based to habit-based actions. This suggests that there are changes in prefrontal and dorsal striatal circuits that underlie these different types of behaviors. Support for this hypothesis comes from imaging studies that reveal alterations in prefrontal and striatal brain regions in alcoholic subjects as compared to non-alcoholic controls. Studies proposed in this research component will examine how changes in corticostriatal neural networks may underlie the transition from controlled, decision-based drinking to compulsive and habitual alcohol consumption. These studies use a well-characterized mouse model of dependence that involves repeated cycles of chronic intermittent ethanol (CIE) exposure and withdrawal that results in escalation of alcohol self-administration. Advanced multi-electrode array recording procedures will be used to measure neuronal population activity within discrete corticostriatal networks during performance of cognitive behavioral tasks that engage prefrontal networks. We hypothesize that repeated cycles of CIE exposure alters the dynamics of prefrontal cortical networks leading to impaired executive function and ultimately loss of inhibitory control by the prefrontal cortex (PFC) over drinking. This hypothesis will be tested using four specific aims that will: 1) Determine whether CIE exposure-induced escalations in drinking are associated with the transition from goal-directed to habitual control;2) Determine whether CIE exposure-induced escalation in drinking is associated with the development of deficits in working memory as an index of executive dysfunction;3) Use multi-electrode recording procedures to assess alterations in corticostriatal networks during repeated cycles of CIE exposure;and 4) Determine whether aripiprazole, a compound demonstrated during the previous funding cycle to reduce drinking in both mice and humans, reverses CIE exposure-induced deficits in working memory. The results of these studies will fundamentally advance our understanding of the role of neuroadaptive changes in corticostriatal networks in the development of alcohol addiction and dependence, and will lay the groundwork for future studies targeting executive function as a new pharmaco-therapeutic approach for more effective treatment of this devastating disorder.

Public Health Relevance

Alcoholism is a chronic relapsing disorder that is characterized by loss of control over drinking. Accumulating evidence suggests that prolonged and excessive alcohol consumption changes the brain so that it can no longer control drinking. Studies in this project will examine how chronic alcohol exposure changes brain activity in regions that control cognitive and habitual behaviors, thereby leading to addiction to and dependence on alcohol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA010761-18
Application #
8434187
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
18
Fiscal Year
2013
Total Cost
$211,842
Indirect Cost
$67,540
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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