ADAR2-dependent GluA2 editing regulates cocaine seeking
| Autor: | R. C. Pierce, Ghazaleh Sadri-Vakili, Gavin R. Sangrey, Shayna B. Darnell, Jang-Ho J. Cha, Heath D. Schmidt, Karen N. McFarland, Megan N. Huizenga |
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| Rok vydání: | 2014 |
| Předmět: |
Male
RNA editing Adenosine Deaminase media_common.quotation_subject Drug-Seeking Behavior psychostimulant Self Administration AMPA receptor Nucleus accumbens Epigenetics of cocaine addiction Pharmacology Nucleus Accumbens Article Rats Sprague-Dawley Cellular and Molecular Neuroscience Cocaine Dopamine Uptake Inhibitors Transduction Genetic ADAR2 Animals RNA Messenger Receptors AMPA Deoxyribonucleases Type II Site-Specific Receptor Molecular Biology media_common relapse Addiction Rats Psychiatry and Mental health Gene Expression Regulation nervous system Conditioning Operant Calcium addiction Psychopharmacology Psychology Self-administration |
| Zdroj: | Molecular psychiatry |
| ISSN: | 1476-5578 1359-4184 |
| Popis: | Activation of AMPA receptors in the nucleus accumbens is necessary for the reinstatement of cocaine-seeking behavior, an animal model of drug craving and relapse. AMPA receptors are tetrameric protein complexes that consist of GluA1-GluA4 subunits, of which GluA2 imparts calcium permeability. Adenosine deaminase acting on RNA (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 AMPA receptors (CP-AMPARs), whereas edited GluA2(R) subunits form calcium impermeable channels (CIAMPARs). 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 to yoked saline controls. In order 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. |
| Databáze: | OpenAIRE |
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