Alcoholism is a chronic relapsing disorder that continues to be a serious medical and social problem in the U.S. and enhanced efforts are needed to treat it. Advances in our understanding about mechanisms underlying motivation to drink and, in particular, mechanisms that drive transition from moderate drinking to more excessive and uncontrolled drinking are key to developing new and more effective treatment strategies. A contemporary view of alcohol addiction is that adaptations in glutamate (GLU) and dopamine (DA) transmission within regions of the striatum (key components of neurocircuitry that mediate motivated behavior) play a significant role in regulation of ethanol drinking behavior. While our current research efforts have focused on neurochemical adaptations in the ventral striatum (i.e., nucleus accumbens;NAc), recent evidence suggests that adaptations in GLU and DA transmission in the dorsolateral striatum (DLS) may play a prominent role in mediating the transition from controlled drinking to uncontrolled compulsive drinking that is characteristic of ethanol dependence. Accordingly, the overall objective of this proposal is to examine adaptations in GLU and DA transmission in dorsal striatum that may qualitatively or quantitatively differ from those in ventral striatum, as well as evaluate the influence of pharmacotherapeutics on voluntary ethanol drinking and neurochemical alterations that may underlie motivation to drink in dependent compared to nondependent animals. A guiding principle of the proposal is that ethanol dependence is associated with adaptations in GLU and DA transmission within dorsolateral striatum and that play an integral role in driving transition from moderate controlled drinking to uncontrolled excessive drinking. The research plan entails use of an established mouse model of ethanol dependence and relapse drinking along with in vivo microdialysis procedures to characterize changes in extracellular levels of GLU and DA in dorsal compared to ventral regions of the striatum that are associated with escalation of voluntary ethanol drinking in dependent mice compared to stable intake exhibited by nondependent mice. Additionally, these studies will provide new information on potential neuroanatomical sites and neurochemical mechanisms underlying the ability of pharmacological treatments to reduce excessive ethanol drinking associated with dependence, which could lead to new insights and approaches in the development of more effective pharmacotherapies for the treatment of alcoholism.

Public Health Relevance

Alcoholism is a chronic relapsing disease that represents a serious public health concern. Understanding mechanisms that underlie motivation to drink and, especially, transition to uncontrolled drinking is critical for developing new and more effective treatment strategies. Accordingly, this project focuses on identifying neurochemical changes in the brain that are associated with excessive drinking in dependence, as well as evaluating the ability of drug treatments to prevent or reverse these potentially harmful consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA010761-19
Application #
8601275
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
$200,230
Indirect Cost
$63,764
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