期刊
BIOLOGICAL PSYCHIATRY
卷 84, 期 12, 页码 867-880出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2018.04.009
关键词
Basolateral amygdala; Dorsal striatum; Gene expression; Nucleus accumbens; Prefrontal cortex; RNA sequencing; Ventral hippocampus
资金
- National Institute on Drug Abuse [T32-DA007135-31, P01DA008227, R01DA007359, K99DA04211, K01MH103473, K01DA038654]
- NATIONAL INSTITUTE OF MENTAL HEALTH [K01MH103473] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA007135, K01DA038654, P01DA008227, R37DA007359, R01DA007359] Funding Source: NIH RePORTER
BACKGROUND: Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD). METHODS: We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes. RESULTS: We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context reexposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index-a composite score of several addiction-like behaviors during cocaine SA-in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors. CONCLUSIONS: This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
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