Cocaine Reinstatement and AMPA Receptor Trafficking

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Characterized by high rates of relapse, cocaine addiction remains a serious public health issue for which no effective treatments are currently available. Cocaine relapse is commonly modeled in rodents using the reinstatement paradigm. A growing body of evidence indicates that changes in glutamate transmission and receptor function in the core and shell subregions of the nucleus accumbens play a key role in cocaine priming-induced reinstatement of drug seeking. Importantly, cocaine reinstatement is associated with increased calcium-calmodulin dependent kinase (CaMK) II-mediated phosphorylation of AMPA glutamate receptor subtype 1 (GluA1, previously GluR1) subunits and increased GluA1-containing AMPA receptor surface expression in the nucleus accumbens shell. However, the specific role of CAMKII and the underlying mechanisms for GluA1 subunit trafficking in the nucleus accumbens during the reinstatement of cocaine seeking remains unclear. Trafficking of GluA1-containing AMPA receptors from intracellular pools to synapses relies on chaperone proteins such as stargazin and synapse- associated protein 97 (SAP97), which are also phosphorylated by CaMKII. However, the specific function of these chaperone proteins in cocaine priming-induced reinstatement has yet to be elucidated. The goal of this NRSA proposal is to train the applicant in the use of behavioral and biochemical techniques to determine whether cocaine-seeking behavior results, at least in part, from CaMKII-mediated interactions of GluA1 subunits with stargazin and SAP97. Stargazin and SAP97 associations with GluA1 subunits are postulated to increase trafficking of GluA1-containing AMPA receptors to the plasma membrane in the accumbens shell, but not the core, during cocaine reinstatement. The execution, analysis, and interpretations of the cellular and molecular experiments outlined in this proposal, as well as additional coursework and scientific collaborations, should provide the applicant with the experience necessary to begin a career in basic science research at an academic institution. Further, a more complete understanding of the molecular processes underlying cocaine reinstatement could lead to the development of novel treatments for cocaine craving and addiction. PUBLIC HEALTH RELEVANCE: Cocaine addiction is an ongoing public health problem for which no effective therapeutic treatments are currently available. Exploring the underlying biochemical mechanisms of addiction and relapse in an animal model could identify novel pharmacotherapeutic targets for the treatment of cocaine addiction and craving. The results from these studies may pave the way for the development of new interventions for cocaine addiction.