title: ADAR2-dependent GluA2 editing regulates cocaine seeking.
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.
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Schmidt
authors.affiliation: Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: McFarland
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Darnell
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Huizenga
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Sangrey
authors.affiliation: Merck, North Wales, PA, USA.
authors.forename: J-H J
authors.initials: JH
authors.lastname: Cha
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Pierce
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sadri-Vakili
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D015252:Deoxyribonucleases, Type II Site-Specific / Q000008:administration & dosage; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017393:RNA Editing / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration; D014161:Transduction, Genetic
chemical_list: D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D018091:Receptors, AMPA; C074997:endodexoyribonuclease BbvI; D015252:Deoxyribonucleases, Type II Site-Specific; C000602621:Adarb1 protein, rat; D000243:Adenosine Deaminase; D003042:Cocaine; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium