Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Nat Neurosci. 2013 Aug;16(8):1111-7. doi: 10.1038/nn.3439. Epub 2013 Jun 23.

Abstract

Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval during a memory reconsolidation process that depends on protein synthesis. Here we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates are crucial in alcohol-related memory reconsolidation and highlight this pathway as a therapeutic target to prevent relapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Amygdala / physiopathology*
  • Animals
  • Anisomycin / pharmacology*
  • Anisomycin / therapeutic use
  • Binge Drinking / prevention & control
  • Binge Drinking / psychology*
  • Conditioning, Operant / physiology
  • Cues
  • Ethanol / blood
  • Ethanol / chemistry
  • Ethanol / pharmacology
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Memory / drug effects*
  • Memory / physiology
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / physiology
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Neuronal Plasticity
  • Odorants
  • Phosphorylation / drug effects
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology*
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / physiology
  • Protein Processing, Post-Translational / drug effects
  • Rats
  • Rats, Long-Evans
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sirolimus / pharmacology*
  • Sirolimus / therapeutic use
  • Spatial Behavior / drug effects
  • Spatial Behavior / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / physiology
  • Taste

Substances

  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Ethanol
  • Anisomycin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus