title: Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition.
abstract: BACKGROUND
  Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction.
  
  
  OBJECTIVE
  The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory.
  
  
  METHODS
  Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine.
  
  
  RESULTS
  Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories.
  
  
  CONCLUSIONS
  These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.
authors.affiliation: Department of Pharmacology and the Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Xiangdang
authors.initials: X
authors.lastname: Shi
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Miller
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Harper
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Poole
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Unterwald
mesh_terms: D000818:Animals; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000187:drug effects / Q000523:psychology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008568:Memory / Q000187:drug effects; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000502:physiology*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; C417521:SB 216763; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3