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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grakalic, Ivana
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
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Cannady, Reginald; Fisher, Kristen R; Graham, Caitlin et al. (2017) Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner. Addict Biol 22:652-664
Salling, Michael C; Faccidomo, Sara P; Li, Chia et al. (2016) Moderate Alcohol Drinking and the Amygdala Proteome: Identification and Validation of Calcium/Calmodulin Dependent Kinase II and AMPA Receptor Activity as Novel Molecular Mechanisms of the Positive Reinforcing Effects of Alcohol. Biol Psychiatry 79:430-42
Agoglia, Abigail E; Sharko, Amanda C; Psilos, Kelly E et al. (2015) Alcohol alters the activation of ERK1/2, a functional regulator of binge alcohol drinking in adult C57BL/6J mice. Alcohol Clin Exp Res 39:463-75
Faccidomo, Sara; Salling, Michael C; Galunas, Christina et al. (2015) Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice. Psychopharmacology (Berl) 232:3417-30
Agoglia, Abigail E; Holstein, Sarah E; Reid, Grant et al. (2015) CaMKII?-GluA1 Activity Underlies Vulnerability to Adolescent Binge Alcohol Drinking. Alcohol Clin Exp Res 39:1680-90
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
Robinson, J Elliott; Chen, Meng; Stamatakis, Alice M et al. (2013) Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice. Neuropsychopharmacology 38:1322-33
Riday, Thorfinn T; Dankoski, Elyse C; Krouse, Michael C et al. (2012) Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. J Clin Invest 122:4544-54
Spanos, Marina; Besheer, Joyce; Hodge, Clyde W (2012) Increased sensitivity to alcohol induced changes in ERK Map kinase phosphorylation and memory disruption in adolescent as compared to adult C57BL/6J mice. Behav Brain Res 230:158-66

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