Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders.
Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce the activation of the mTORC1-mediated signaling pathway in the nucleus accumbens (NAc) of rodents. We further show that the protein expression levels of GluR1 and Homer, two synaptic proteins whose translation has been shown to be modulated by mTORC1, are up-regulated in the NAc of rodents with a history of excessive alcohol consumption. In addition, our results document that the Food and Drug Administration-approved inhibitor of mTORC1, rapamycin, decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking in preclinical rodent models of alcohol abuse. Together, our results suggest that mTORC1 within the NAc is a contributor to molecular mechanisms underlying alcohol-drinking behaviors. Furthermore, despite its massive health and socioeconomic impact worldwide, pharmacotherapies for alcohol abuse and addiction remain limited. Our data therefore put forward the possibility that targeting the mTORC1 signaling cascade is an innovative and valuable strategy for the treatment of alcohol use and abuse disorders.
Ernest Gallo Research Center and Department of Neurology, University of California, San Francisco, CA 94608, USA.
Jérémie
J
Neasta
Sami
S
Ben Hamida
Quinn
Q
Yowell
Sebastien
S
Carnicella
Dorit
D
Ron
D000222:Adaptation, Physiological / Q000187:drug effects; D019973:Alcohol-Related Disorders / Q000503:physiopathology*; D000438:Alcohols / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D046912:Multiprotein Complexes; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000438:Alcohols; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D018091:Receptors, AMPA; D020123:Sirolimus; D013395:Sucrose; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C519510:Crtc1 protein, rat