title: Phosphoproteomic Analysis Reveals a Novel Mechanism of CaMKIIα Regulation Inversely Induced by Cocaine Memory Extinction versus Reconsolidation.
abstract: Successful addiction treatment depends on maintaining long-term abstinence, making relapse prevention an essential therapeutic goal. However, exposure to environmental cues associated with drug use often thwarts abstinence efforts by triggering drug using memories that drive craving and relapse. We sought to develop a dual approach for weakening cocaine memories through phosphoproteomic identification of targets regulated in opposite directions by memory extinction compared with reconsolidation in male Sprague-Dawley rats that had been trained to self-administer cocaine paired with an audiovisual cue. We discovered a novel, inversely regulated, memory-dependent phosphorylation event on calcium-calmodulin-dependent kinase II α (CaMKIIα) at serine (S)331. Correspondingly, extinction-associated S331 phosphorylation inhibited CaMKIIα activity. Intra-basolateral amygdala inhibition of CaMKII promoted memory extinction and disrupted reconsolidation, leading to a reduction in subsequent cue-induced reinstatement. CaMKII inhibition had no effect if the memory was neither retrieved nor extinguished. Therefore, inhibition of CaMKII represents a novel mechanism for memory-based addiction treatment that leverages both extinction enhancement and reconsolidation disruption to reduce relapse-like behavior.
  
  
  
  Preventing relapse to drug use is an important goal for the successful treatment of addictive disorders. Relapse-prevention therapies attempt to interfere with drug-associated memories, but are often hindered by unintentional memory strengthening. In this study, we identify phosphorylation events that are bidirectionally regulated by the reconsolidation versus extinction of a cocaine-associated memory, including a novel site on CaMKIIα. Additionally, using a rodent model of addiction, we show that CaMKII inhibition in the amygdala can reduce relapse-like behavior. Together, our data supports the existence of mechanisms that can be used to enhance current strategies for addiction treatment.
authors.affiliation: Department of Psychiatry, Center for Neuroscience, and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors.forename: Matthew T
authors.identifier: 0000-0001-6627-4627
authors.initials: MT
authors.lastname: Rich
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Abbott
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: Erol E
authors.initials: EE
authors.lastname: Gulcicek
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Stone
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: Christopher M
authors.identifier: 0000-0002-0438-1395
authors.initials: CM
authors.lastname: Colangelo
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale/Keck MS and Proteomics Resource, Yale University, New Haven, Connecticut 06511-6624, and.
authors.forename: TuKiet T
authors.identifier: 0000-0002-4850-3462
authors.initials: TT
authors.lastname: Lam
authors.affiliation: Departments of Psychiatry, Pharmacology, and.
authors.forename: Angus C
authors.identifier: 0000-0002-7075-0195
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Departments of Psychiatry, Psychology, Yale University, New Haven, Connecticut 06520.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
authors.affiliation: Department of Psychiatry, Center for Neuroscience, and torregrossam@upmc.edu.
authors.forename: Mary M
authors.identifier: 0000-0003-2083-0231
authors.initials: MM
authors.lastname: Torregrossa
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; D004791:Enzyme Inhibitors; D012694:Serine; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C063302:KN 62
keywords: CaMKIIa; cocaine; extinction; proteomics; reconsolidation; reinstatement