Research Component 1 - Hodge 'Molecular Mechanisms of Drinking and Relapse' Alcoholism is acomplex neuropsychiatric disorder that is characterized by periods of chronic drinking, abstinence andrelapse. Emerging evidence suggests that ethanol and other drugs of abuse may produce adaptive changesin cell signaling and gene transcription pathways that lead to enduring changes in brain function. Theseadaptations are thought to regulate behavioral pathologies that occur in alcoholism and are of fundamentalimportance for treating the alcoholic in the clinic. The preclinical studies in this application are focused onthe mitogen-activated protein kinase (MARK) cell signaling pathway as a novel molecular mechanism ofalcohol-related behavioral pathologies. We have discovered that extracellular-regulated MAP kinase(ERK1/2) activity adapts to both chronic alcohol drinking and abstinence, and that ERK1/2 functionallyregulates alcohol self-administration in mouse models. These findings suggest the primary hypothesis ofthis application: voluntary alcohol self-administration and abstinence lead to adaptations in the ERK1/2signaling pathway that functionally regulate behavioral pathologies associated with alcoholism, such asrelapse. The studies in this application have three separate but integrated Specific Aims. First, experimentswill elucidate molecular and cellular neuroadaptations in the ERK/MAPK system that are associated withchronic voluntary alcohol drinking, abstinence, and re-exposure to ethanol. These studies will provide novelinformation on the effect of voluntary drinking on this key molecular pathway throughout the brain. Second,studies will investigate the functional neural circuitry of ERK/MAPK regulation of relapse to alcohol drinking.This will be accomplished using a behavioral pharmacology approach coupled with systemic and brain sitespecificmicroinjection of specific MAPK inhibitors. These studies will establish a direct link betweenERK/MAPK activity and relapse-like behavior in an animal model. Third, experiments are proposed tocharacterize ERK/MAPK regulation of ethanol reinforcement during operant self-administration and relapse.The ability of a drug to serve as a positive reinforcer is a fundamental requirement for drug-seeking behaviorand may account for increases in alcohol consumption during relapse. Thus, these studies examineERK/MAPK regulation of a behavioral process that is fundamental to the development of alcoholism. As anintegrated whole, the components of this Center Grant examine a continuum of pathologies ranging frominitial adaptations to tissue damage.
The aims of this Component specifically address molecularmechanisms of behavioral pathologies that occur in the early stages of alcoholism. These early adaptationsmay subserve the progressive pathology associated with alcoholism.
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