AMYGDALA AMPA GLUR2 DELETION AND OPIOID DEPENDENCE

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DESCRIPTION (provided by applicant): Opioid dependence is a major complication of chronic opioid use that contributes to the syndrome of addiction. In addition to the avoidance of withdrawal symptoms, experience of withdrawal-associated cues may also play an important role in drug taking behavior. Thus, elucidating the neurobiological processes that mediate the adverse consequences of chronic opioid use, particularly involving the role of aversive learning, may provide critical information for managing addictive disease. There is evidence that ionotropic AMPA-type glutamate receptors in the central nucleus of the amygdala (CeA) may be important molecular substrates of opioid dependence. The AMPA-GluR2 (GluR2) receptor subunit is a major component of AMPA receptors, determines calcium permeability, has been implicated in drug dependence, and is expressed in the CeA. The activity of GluR2 expressing AMPA receptors is modulated by NMDA-type glutamate receptors, which are themselves, established molecular substrates of neural and behavioral adaptability. Despite these findings, there is no direct evidence that GluR2 gene expression in the CeA is necessary for the expression of opioid dependence. The primary goal of this application is to develop a spatial-temporal deletion of the AMPA-GluR2 receptor subunit to test the hypothesis that postsynaptic expression of GluR2 in central amygdala neurons is necessary for opioid withdrawal- induced conditioned place aversion (CPA). This hypothesis will be investigated by producing a postsynaptic deletion of GluR2 in central amygdala neurons of floxed GluR2 mice via local microinjection of a neurotropic adenoassociated viral vector expressing Cre recombinase. The viability of local gene deletion will be tested by light and electron immunohistochemistry and in situ hybridization. The phenotypic effects of CeA GluR2 deletion will be determined by behavioral measurements, including withdrawal-induced conditioned place aversion. This project is expected to enhance our understanding of the role of neuronal glutamate receptor gene expression in opioid dependence, particularly with respect to the possible value of AMPA-GluR2 based small molecule or gene therapeutics. Despite the clinical efficacy of opioids, their abuse and addictive liabilities are significant sources of public health problems. Opioids may produce their long-lasting effects by activating amygdala glutamate receptors, molecules that play important roles in neural plasticity, as well as learning and memory. Using state of the art molecular neuropharmacological techniques, this proposal will identify the role of the AMPA-type glutamate receptor GluR2 subunit in the amygdala with respect to opioid dependence. By elucidating the neurobiological processes that mediate the adverse consequences of dependence, we may provide critical information needed to develop pharmacological interventions for reducing these deleterious actions.