title: Dorsal hippocampal NMDA receptor blockade impairs extinction of naloxone-precipitated conditioned place aversion in acute morphine-treated rats by suppressing ERK and CREB phosphorylation in the basolateral amygdala.
abstract: OBJECTIVE
  Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying the loss (extinction) of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction.
  
  
  METHODS
  Naloxone-induced conditioned place aversion (CPA) of Sprague-Dawley rats was used to measure conditioned aversion. An NMDA receptor antagonist and MAPK kinase inhibitor were applied through intracranial injections. The phosphorylation of ERK and cAMP response element-binding protein (CREB) was detected using Western blot.
  
  
  RESULTS
  The extinction of CPA behaviour increased the phosphorylation of ERK and CREB in the dorsal hippocampus (DH) and basolateral amygdala (BLA), but not in the central amygdala (CeA). Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuated ERK and CREB phosphorylation in the BLA and impaired the extinction of CPA behaviour. Although intra-DH injections of AP-5 attenuated extinction training-induced activation of the ERK-CREB pathway in the BLA, intra-BLA injection of AP5 had no effect on extinction training-induced activation of the ERK-CREB pathway in the DH.
  
  
  CONCLUSIONS
  These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behaviour and that the DH, via a direct or indirect pathway, modulates the activity of ERK and CREB in the BLA through activation of NMDA receptors after extinction training. Understanding the mechanisms underlying the extinction of conditioned aversion could facilitate the treatment of drug addiction.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Drug Research, Key Laboratory of Receptor Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Wang
authors.forename: Zhong-Guo
authors.initials: ZG
authors.lastname: Chen
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Liu
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chi
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D009292:Narcotic Antagonists; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C113580:U 0126; D009270:Naloxone; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: amygdala; drug withdrawal; extinction; hippocampal