title: Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine.
abstract: Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)-whose disruption is postulated to increase vulnerability to drug addiction-was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Andon N
authors.initials: AN
authors.lastname: Placzek
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Viana Di Prisco
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Khatiwada
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Carmela
authors.initials: C
authors.lastname: Sidrauski
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Krešimir
authors.initials: K
authors.lastname: Krnjević
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, Philadelphia, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Dani
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Mauro
authors.identifier: http://orcid.org/0000-0002-9809-4732
authors.initials: M
authors.lastname: Costa-Mattioli
mesh_terms: D000818:Animals; D001519:Behavior / Q000187:drug effects*; D003042:Cocaine / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D013569:Synapses / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D003042:Cocaine
keywords: cocaine; long-term depression (LTD); long-term potentiation (LTP); mouse; neuroscience; protein synthesis; ventral tegemental area