Alcoholism is a complex neuropsychiatric disorder that is characterized by periods of chronic drinking, abstinence and relapse. Emerging evidence suggests that ethanol and other drugs of abuse may produce adaptive changes in cell signaling and gene transcription pathways that lead to enduring changes in brain function. These adaptations are thought to regulate behavioral pathologies that occur in alcoholism and are of fundamental importance for treating the alcoholic in the clinic. The preclinical studies in this application are focused on calcium/calmodulin-dependent protein kinase II (CaMKII) as a novel molecular mechanism of alcohol-related behavioral pathologies. We have discovered that voluntary alcohol drinking increases CaMKII1 protein expression in mouse amygdala and that reinstatement of alcohol-seeking behavior is associated with increased CaMKII activation in the lateral amygdala, a sub-nucleus of the amygdala where CaMKII is known to regulate associative learning. These findings suggest the primary hypothesis of this application: voluntary alcohol self- administration and abstinence lead to adaptations in CaMKII signaling that functionally regulate behavioral pathologies associated with alcoholism, such as relapse. The studies in this application have three separate but integrated Specific Aims. First, experiments will elucidate molecular and cellular neuroadaptations in CaMKII that are associated with chronic voluntary alcohol drinking and abstinence. These studies will provide novel information on the effect of voluntary drinking on this key molecular pathway throughout the brain. Second, studies will investigate the functional neural circuitry of CaMKII regulation of alcohol reinforcement. This will be accomplished using a behavioral pharmacology approach coupled with brain site-specific microinjection of specific CaMKII inhibitors. These studies will establish a direct link between CaMKII activity and the reinforcing effects of alcohol that maintain chronic drinking. Third, experiments are proposed to characterize CaMKII regulation of relapse-like behavior using a mouse model of reinstatement of alcohol-seeking behavior. Thus, these studies examine CaMKII regulation of behavioral processes that are fundamental to the development and progression of alcoholism. A better understanding of the molecular and cellular mechanisms that regulate behavioral pathologies in alcoholism has the potential to lead to new pharmacotherapeutic strategies.

Public Health Relevance

Chronic alcohol use and relapse after periods of abstinence are hallmark behavioral pathologies of alcoholism and a major clinical problem. Emerging evidence suggests that neuroadaptations in cell signaling and gene transcription pathways mediate relapse and other behavioral pathologies in alcohol and drug abuse. Thus, the overall goal of the preclinical studies in this renewal application is to identify and validate molecular and cellular mechanisms of alcohol reinforcement and relapse-like behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA014983-09
Application #
8688097
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2004-04-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Cook, Jason B; Werner, David F; Maldonado-Devincci, Antoniette M et al. (2014) Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3α,5α-THP and reduces long-term operant ethanol self-administration. J Neurosci 34:5824-34
Hay, Rachel A; Jennings, Joshua H; Zitzman, Dawnya L et al. (2013) Specific and nonspecific effects of naltrexone on goal-directed and habitual models of alcohol seeking and drinking. Alcohol Clin Exp Res 37:1100-10
Cannady, Reginald; Fisher, Kristen R; Durant, Brandon et al. (2013) Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol 18:54-65

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