ADAR2-dependent GluA2 editing regulates cocaine seeking

Mol Psychiatry. 2015 Nov;20(11):1460-6. doi: 10.1038/mp.2014.134. Epub 2014 Oct 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Animals
  • Calcium / metabolism
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Deoxyribonucleases, Type II Site-Specific / administration & dosage
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Drug-Seeking Behavior / drug effects*
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • RNA Editing / drug effects
  • RNA Editing / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Self Administration
  • Transduction, Genetic

Substances

  • Dopamine Uptake Inhibitors
  • RNA, Messenger
  • Receptors, AMPA
  • endodexoyribonuclease BbvI
  • Deoxyribonucleases, Type II Site-Specific
  • Adarb1 protein, rat
  • Adenosine Deaminase
  • Cocaine
  • glutamate receptor ionotropic, AMPA 2
  • Calcium