title: mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) has an essential role in dendritic mRNA translation and participates in mechanisms underlying alcohol-drinking and reconsolidation of alcohol-related memories. Here, we report that excessive alcohol consumption increases the translation of downstream targets of mTORC1, including collapsin response mediator protein-2 (CRMP-2), in the nucleus accumbens (NAc) of rodents. We show that alcohol-mediated induction of CRMP-2 translation is mTORC1-dependent, leading to increased CRMP-2 protein levels. Furthermore, we demonstrate that alcohol intake also blocks glycogen synthase kinase-3β (GSK-3β)-phosphorylation of CRMP-2, which results in elevated binding of CRMP-2 to microtubules and a concomitant increase in microtubule content. Finally, we show that systemic administration of the CRMP-2 inhibitor lacosamide, or knockdown of CRMP-2 in the NAc decreases excessive alcohol intake. These results suggest that CRMP-2 in the NAc is a convergent point that receives inputs from two signaling pathways, mTORC1 and GSK-3β, that in turn drives excessive alcohol-drinking behaviors.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Laguesse
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Legastelois
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Morisot
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ben Hamida
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ron
mesh_terms: D000081:Acetamides; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D003712:Dendrites / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D000078334:Lacosamide; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000081:Acetamides; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D000431:Ethanol; D000078334:Lacosamide; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3