Inhibition of Lactate Transport Erases Drug Memory and Prevents Drug Relapse

Biol Psychiatry. 2016 Jun 1;79(11):928-39. doi: 10.1016/j.biopsych.2015.07.007. Epub 2015 Jul 21.

Abstract

Background: Drug memories that associate drug-paired stimuli with the effects of abused drugs contribute to relapse. Exposure to drug-associated contexts causes consolidated drug memories to be in a labile state, during which manipulations can be given to impair drug memories. Although substantial evidence demonstrates the crucial role of neuronal signaling in addiction, little is known about the contribution of astrocyte-neuron communication.

Methods: Rats were trained for cocaine-induced conditioned place preference (CPP) or self-administration and microinjected with the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol into the basolateral amygdala (BLA) immediately after retrieval. The concentration of lactate was measured immediately after retrieval via microdialysis, and the CPP score and number of nosepokes were recorded 24 hours later. Furthermore, we used antisense oligodeoxynucleotides to disrupt the expression of astrocytic lactate transporters (monocarboxylate transporters 1 and 2) in the BLA after retrieval, tested the expression of CPP 1 day later, and injected L-lactate into the BLA 15 minutes before retrieval to rescue the effects of the oligodeoxynucleotides.

Results: Injection of 1,4-dideoxy-1,4-imino-D-arabinitol into the BLA immediately after retrieval prevented the subsequent expression of cocaine-induced CPP, decreased the concentration of lactate in the BLA, and reduced the number of nosepokes for cocaine self-administration. Disrupting the expression of monocarboxylate transporters 1 and 2 in the BLA also caused subsequent deficits in the expression of cocaine-induced CPP, which was rescued by pretreatment with L-lactate.

Conclusions: Our results suggest that astrocyte-neuron lactate transport in the BLA is critical for the reconsolidation of cocaine memory.

Keywords: Basolateral amygdale; Cocaine; Lactate transport; Reconsolidation; Relapse; Retrieval.

MeSH terms

  • Animals
  • Arabinose / pharmacology*
  • Basolateral Nuclear Complex / drug effects
  • Basolateral Nuclear Complex / metabolism
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / metabolism
  • Cocaine-Related Disorders / psychology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology
  • Imino Furanoses / pharmacology*
  • Lactic Acid / metabolism*
  • Male
  • Memory Consolidation / drug effects*
  • Memory Consolidation / physiology
  • Monocarboxylic Acid Transporters / antagonists & inhibitors
  • Monocarboxylic Acid Transporters / metabolism
  • Psychotropic Drugs / pharmacology*
  • Rats, Sprague-Dawley
  • Recurrence
  • Secondary Prevention
  • Self Administration
  • Space Perception / drug effects
  • Space Perception / physiology
  • Sugar Alcohols / pharmacology*

Substances

  • Dopamine Uptake Inhibitors
  • Imino Furanoses
  • Monocarboxylic Acid Transporters
  • Psychotropic Drugs
  • Sugar Alcohols
  • 1,4-dideoxy-1,4-iminoarabinitol
  • Lactic Acid
  • Arabinose
  • Cocaine