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

Br J Pharmacol. 2015 Jan;172(2):482-91. doi: 10.1111/bph.12671. Epub 2014 Jul 1.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Linked articles: 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.

Keywords: amygdala; drug withdrawal; extinction; hippocampal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology*
  • Basolateral Nuclear Complex / drug effects
  • Basolateral Nuclear Complex / metabolism
  • Basolateral Nuclear Complex / physiology*
  • Butadienes / pharmacology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology*
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Male
  • Morphine / pharmacology
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / physiology

Substances

  • Analgesics, Opioid
  • Butadienes
  • Cyclic AMP Response Element-Binding Protein
  • Narcotic Antagonists
  • Nitriles
  • Protein Kinase Inhibitors
  • Receptors, N-Methyl-D-Aspartate
  • U 0126
  • Naloxone
  • Morphine
  • Extracellular Signal-Regulated MAP Kinases