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Neuropsychiatric disorders such as anxiety, depression, and substance use disorders are highly prevalent disorders and immensely costly to society. Treatment options are limited, and cocaine use disorder in particular, has no FDA approved pharmacotherapeutic. These disorders are highly comorbid and are often more severe when they co-occur. Thus, it is critical to determine novel targets for substance use disorders with comorbid mood disorders. In order to identify novel targets, we examine an animal model of the resilience to depression and addiction, environmental enrichment. Environmental enrichment is a non-drug, non-surgical, non-genetic manipulation that produces protective depression and addiction phenotypes. Enriched rats are reared in a large cage with conspecifics and plastic toys that are changed and rearranged daily. Most individuals that use addictive substances do not become addicted. Environmental enrichment mimics these individual differences in susceptibility. Therefore, the overall goal of this study is to identify novel therapeutic targets for treating neuropsychiatric disorders using two discovery-based strategies. The first strategy to narrow the exciting leads is a convergent transcriptomic/proteomic analysis of mRNA and protein regulated by enrichment and cocaine. This strategy identifies AKT signaling as a promising pathway; therefore, we knocked down the downstream target of AKT, glycogen synthase kinase 3 (GSK3) beta, with a novel adeno-associated viral (AAV) vector in the nucleus accumbens shell (NAcSh) of rats and found increases in depression-like and cocaine taking behaviors. Additionally, GSK3 …