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Elife. 2016 Mar 1;5. pii: e12052. doi: 10.7554/eLife.12052.

Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine.

Author information

1
Department of Neuroscience, Baylor College of Medicine, Houston, United States.
2
Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
3
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
5
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
6
Department of Physiology, McGill University, Montreal, Canada.
7
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, Philadelphia, United States.

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.

KEYWORDS:

cocaine; long-term depression (LTD); long-term potentiation (LTP); mouse; neuroscience; protein synthesis; ventral tegemental area

Comment in

PMID:
26928234
PMCID:
PMC4786430
DOI:
10.7554/eLife.12052
[Indexed for MEDLINE]
Free PMC Article

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