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ADAR2-dependent GluA2 editing regulates cocaine seeking

Molecular Psychiatry volume 20, pages 1460–1466 (2015)Cite this article

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Abstract

Activation of AMPA receptors (AMPARs) in the nucleus accumbens is necessary for the reinstatement of cocaine-seeking behavior, an animal model of drug craving and relapse. AMPARs are tetrameric protein complexes that consist of GluA1–4 subunits, of which GluA2 imparts calcium permeability. Adenosine deaminase acting on RNA 2 (ADAR2) is a nuclear enzyme that is essential for editing GluA2 pre-mRNA at Q/R site 607. Unedited GluA2(Q) subunits form calcium-permeable AMPARs (CP-AMPARs), whereas edited GluA2(R) subunits form calcium-impermeable channels (CI-AMPARs). Emerging evidence suggests that the reinstatement of cocaine seeking is associated with increased synaptic expression of CP-AMPARs in the nucleus accumbens. However, the role of GluA2 Q/R site editing and ADAR2 in cocaine seeking is unclear. In the present study, we investigated the effects of forced cocaine abstinence on GluA2 Q/R site editing and ADAR2 expression in the nucleus accumbens. Our results demonstrate that 7 days of cocaine abstinence is associated with decreased GluA2 Q/R site editing and reduced ADAR2 expression in the accumbens shell, but not core, of cocaine-experienced rats compared with yoked saline controls. To examine the functional significance of ADAR2 and GluA2 Q/R site editing in cocaine seeking, we used viral-mediated gene delivery to overexpress ADAR2b in the accumbens shell. Increased ADAR2b expression in the shell attenuated cocaine priming-induced reinstatement of drug seeking and was associated with increased GluA2 Q/R site editing and surface expression of GluA2-containing AMPARs. Taken together, these findings support the novel hypothesis that an increased contribution of accumbens shell CP-AMPARs containing unedited GluA2(Q) promotes cocaine seeking. Therefore, CP-AMPARs containing unedited GluA2(Q) represent a novel target for cocaine addiction pharmacotherapies.

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Acknowledgements

We thank Dr Mary O’Connell for her advice and expertise on ADAR2b antibodies. This work was supported by DA022339 (HDS, RCP and GS-V), DA033641 (HDS, RCP and GS-V), K02 DA18678 (RCP) and K01 DA030445 (HDS).

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Authors and Affiliations

  1. Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    H D Schmidt & R C Pierce

  2. Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA

    K N McFarland

  3. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA

    S B Darnell, M N Huizenga, G R Sangrey & G Sadri-Vakili

  4. Merck, North Wales, PA, USA

    J-H J Cha

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  1. H D Schmidt
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Correspondence to G Sadri-Vakili.

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Schmidt, H., McFarland, K., Darnell, S. et al. ADAR2-dependent GluA2 editing regulates cocaine seeking. Mol Psychiatry 20, 1460–1466 (2015). https://doi.org/10.1038/mp.2014.134

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