title: Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse.
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.
authors.affiliation: The Ernest Gallo Research Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Segev
authors.initials: S
authors.lastname: Barak
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.forename: Quinn V
authors.initials: QV
authors.lastname: Yowell
authors.forename: Jeremie
authors.initials: J
authors.lastname: Neasta
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Janak
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology* / Q000627:therapeutic use; D063425:Binge Drinking / Q000517:prevention & control / Q000523:psychology*; D003216:Conditioning, Operant / Q000502:physiology; D003463:Cues; D000431:Ethanol / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009473:Neuronal Plasticity; D009812:Odorants; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D013649:Taste
chemical_list: D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D000431:Ethanol; D000841:Anisomycin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus