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Profiling the Neuronal Proteome of the Lateral Amygdala Following Cocaine-Cue Memory Retrieval and Systemic Garcinol Administration

Melissa Monsey, Department of Psychiatry, Yale University

Sustained abstinence from cocaine use is frequently compromised by exposure to environmental stimuli that have previously been strongly associated with drug taking. Such cues trigger memories of the effects of the drug, leading to craving and potential relapse. Our previous work has demonstrated that manipulating cocaine-cue memories by destabilizing them through interfering with the reconsolidation process is one potential therapeutic tool by which to prolong abstinence. We have recently successfully used the naturally-occurring histone acetyltransferase (HAT) inhibitor, garcinol, to block the reconsolidation of a cocaine-cue memory in a manner that is specific to the reactivated memory only, cue-specific, long-lasting and temporally constrained. Additionally, we have found that intra-amygdala garcinol infusion is sufficient to block a cocaine-cue memory. Collectively, these data support the hypothesis that garcinol may be a useful novel therapeutic tool by which to interfere with the reconsolidation of cocaine-cue memories. To enhance the translational potential of this idea, we aim to investigate the signaling transduction pathways in the lateral amygdala (LA) following memory retrieval and garcinol administration by examining neuronal proteomic profiles.

The proposed experiments will provide the groundwork necessary for future studies to further understand how garcinol exerts its effects in the brain. Because of the potential therapeutic use of this novel compound in humans, we believe it is vital to first characterize the underlying signaling transduction pathways by examining large-scale protein expression profiles in the LA, a key site of action of garcinol. Other future studies could also employ a genome-wide expression analysis using RNA sequencing following retrieval and systemic garcinol. While we plan to initially examine changes in proteins, this approach will allow for the identification of potentially novel genes associated with the reconsolidation of cocaine-associated memories. Thus, the proposed series of experiments will not only enhance our current knowledge of how garcinol impairs reconsolidation but will also provide further evidence for its use in the treatment of addictive disorders making this project relevant to the Yale/NIDA Neuroproteomics Center’s theme of Proteomics of Altered Signaling in Addiction.

The specific aim of this project is to investigate how garcinol alters the cocaine-cue memory retrieval-induced neuroproteomic expression profile in the LA. We will first investigate which proteins are differentially expressed in the LA following memory retrieval and garcinol administration by utilizing a high resolution LC MS/MS Label Free Quantitative (LFQ) approach. Next, we will examine levels of Lysine acetylation on proteins in the LA under these conditions utilizing an LFQ MS workflow in conjunction with an acetyl-Lysine Motif enrichment protocol.