Molecular mechanisms of neural plasticity in drug addiction

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): In the U.S., 9% of individuals age 12 and over are considered abusers of one or more substances despite serious negative consequences (Substance Abuse & Mental Health Services Administration, 2008). Human drug abuse typically follows a cycle of abstinence and relapse, the lasting nature of which poses perhaps the greatest challenge to clinical treatment. Since drug-induced sensitization in rodents is used to model the longevity of addiction, understanding mechanisms influencing this behavior, as well as associated brain adaptations, should suggest targets for therapeutic intervention, or possibly, prevention. Recently, it has been shown that chronic cocaine exposure regulates spine density in the nucleus accumbens, the brain's reward center, via cyclic-adenosine monophosphate (cAMP)-dependent inhibition of a transcription factor known as myocyte enhancer factor 2 (MEF2). Furthermore, MEF2 downregulation and spine upregulation are associated with protection against cocaine-induced behavioral sensitization (Pulipparacharuvil et al., 2008). The goal of the current proposal is to determine specific signaling mechanisms responsible for MEF2 regulation, as well as to determine signaling mechanisms involved in cocaine-induced MEF2 regulation, dendritic spine density and behavioral sensitization. Specific aim #1 is to elucidate signaling mechanisms underlying cAMP-dependent inhibition of MEF2. Initial focus will be on whether regulator of calmodulin signaling (RCS), a small neuronal phosphoprotein, is required for this process using neurons cultured from RCS-knockout mice. RNAi-based protein-replacement assays and specific phospho-antibodies to MEF2 Ser408/444 will be used to test the functional role of phosphorylation in cAMP's effect on MEF2, and a calcium-independent form of CaMK will be used to test the involvement of this protein family. Specific aim #2 is to determine the role of RCS in cocaine-dependent regulation of MEF2, spine upregulaton and behavioral sensitization in vivo. This aim will be carried out in a RCS-knockout mouse model of cocaine use in order to determine the necessity of RCS for cocaine-induced changes in each of these areas. Findings from these studies, taken together, will help elucidate how cAMP and cocaine regulate MEF2, and ultimately, how signaling mechanisms in these pathways may contribute to drug-induced spine plasticity and behavioral responses. Relevance: Repeated exposure to drugs of abuse, such as cocaine, is known to cause changes in brain structure and function that may relate to the longevity of addiction. The goal of this project is to understand how these changes occur, which may lead to targets for potential treatment or prevention of addiction.