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Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety

Neuropsychopharmacology (2018) | Download Citation

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Abstract

Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule). Similarly, G9a knockdown reduces motivation for cocaine under higher effort demands (progressive ratio schedule). Following several weeks of forced abstinence, G9a knockdown attenuates extinction responding and reinstatement triggered by either cocaine-priming injections or footshock stress. This decrease in addictive behavior is associated with a long-term reduction in anxiety-like behavior as measured by the elevated plus maze (EPM). G9a knockdown also reduces basal anxiety-like behavior in EPM and marble burying tests in drug-naïve rats. These results complement our previous work showing that increased G9a expression in NAcSh enhances addictive-related and anxiety-related behaviors, indicating that G9a bi-directionally controls these responses. These results also suggest that regulation of G9a-influenced gene expression could be a common epigenetic mechanism for co-morbid anxiety and psychostimulant addiction.

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Acknowledgements

We would like to thank Shari Birnbaum, Ph.D. at the University of Texas Southwestern for her assistance with the elevated plus maze assay. We would also like to thank Dr. Carmela Reichel, Dr. Jacqueline McGinty, Dr. Rhett Reichard, Angela Kearns, and Jordan Hopkins at the Medical University of South Carolina for their assistance with the basal anxiety experiments.

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Affiliations

  1. Department of Psychiatry, The Seay Center for Basic and Applied Research in Psychiatric Illness, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9070, USA

    • Ethan M. Anderson
    • , Daniel Guzman
    •  & David W. Self
  2. Departments of Neuroscience and Psychiatry and Behavioral Sciences, Medical University of South Carolina, 173 Ashley Ave, MSC 510, Charleston, SC, 29425-2030, USA

    • Ethan M. Anderson
    • , Makoto Taniguchi
    •  & Christopher W. Cowan
  3. Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1065, New York, NY, 10029, USA

    • Haosheng Sun
    • , Ian Maze
    •  & Eric J. Nestler

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Correspondence to Ethan M. Anderson.

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DOI

https://doi.org/10.1038/s41386-018-0305-4