eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons

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Abstract

Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1—an mRNA whose translation is controlled by p-eIF2α—in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.

DOI: http://dx.doi.org/10.7554/eLife.17517.001

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Most cited references 29

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Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling.

Christian Lüscher, Robert C Malenka (2011)

Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

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Imaging dopamine's role in drug abuse and addiction.

N D Volkow, J S Fowler, G J Wang … (2009)

Dopamine is involved in drug reinforcement but its role in addiction is less clear. Here we describe PET imaging studies that investigate dopamine's involvement in drug abuse in the human brain. In humans the reinforcing effects of drugs are associated with large and fast increases in extracellular dopamine, which mimic those induced by physiological dopamine cell firing but are more intense and protracted. Since dopamine cells fire in response to salient stimuli, supraphysiological activation by drugs is experienced as highly salient (driving attention, arousal, conditioned learning and motivation) and with repeated drug use may raise the thresholds required for dopamine cell activation and signaling. Indeed, imaging studies show that drug abusers have marked decreases in dopamine D2 receptors and in dopamine release. This decrease in dopamine function is associated with reduced regional activity in orbitofrontal cortex (involved in salience attribution; its disruption results in compulsive behaviors), cingulate gyrus (involved in inhibitory control; its disruption results in impulsivity) and dorsolateral prefrontal cortex (involved in executive function; its disruption results in impaired regulation of intentional actions). In parallel, conditioning triggered by drugs leads to enhanced dopamine signaling when exposed to conditioned cues, which then drives the motivation to procure the drug in part by activation of prefrontal and striatal regions. These findings implicate deficits in dopamine activity-inked with prefrontal and striatal deregulation-in the loss of control and compulsive drug intake that results when the addicted person takes the drugs or is exposed to conditioned cues. The decreased dopamine function in addicted individuals also reduces their sensitivity to natural reinforcers. Therapeutic interventions aimed at restoring brain dopaminergic tone and activity of cortical projection regions could improve prefrontal function, enhance inhibitory control and interfere with impulsivity and compulsive drug administration while helping to motivate the addicted person to engage in non-drug related behaviors.

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Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.

Mark A Ungless, Antonello Bonci, Jennifer Whistler … (2001)

How do drugs of abuse modify neural circuitry and thereby lead to addictive behaviour? As for many forms of experience-dependent plasticity, modifications in glutamatergic synaptic transmission have been suggested to be particularly important. Evidence of such changes in response to in vivo administration of drugs of abuse is lacking, however. Here we show that a single in vivo exposure to cocaine induces long-term potentiation of AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated currents at excitatory synapses onto dopamine cells in the ventral tegmental area. Potentiation is still observed 5 but not 10 days after cocaine exposure and is blocked when an NMDA (N-methyl-d-aspartate) receptor antagonist is administered with cocaine. Furthermore, long-term potentiation at these synapses is occluded and long-term depression is enhanced by in vivo cocaine exposure. These results show that a prominent form of synaptic plasticity can be elicited by a single in vivo exposure to cocaine and therefore may be involved in the early stages of the development of drug addiction.

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Author and article information

Contributors

Rui M Costa: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 13 December 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e17517

Affiliations

[1 ]deptDepartment of Neuroscience , Baylor College of Medicine , Houston, United States

[2 ]deptMemory and Brain Research Center , Baylor College of Medicine , Houston, United States

[3 ]deptVerna and Marrs McLean Department of Biochemistry and Molecular Biology , Baylor College of Medicine , Houston, United States

[4 ]deptDepartment of Physiology , McGill University , Montreal, Canada

[5 ]deptDegenerative Diseases Program , SBP Medical Discovery Institute , La Jolla, United States

[6 ]deptDepartment of Neuroscience , Mahoney Institute for Neurosciences, Perelman School of Medicine , Philadelphia, United States

[7 ]deptDepartment of Biochemistry and Biophysics , Howard Hughes Medical Institute, University of California at San Francisco , San Francisco, United States

[8]Fundação Champalimaud , Portugal

[9]Fundação Champalimaud , Portugal

Author notes

costamat@ 123456bcm.edu

[‡]

Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, United States.

[†]

These authors contributed equally to this work.

Article

Publisher ID: 17517

DOI: 10.7554/eLife.17517

PMC ID: 5154759

PubMed ID: 27960077

SO-VID: 9c7cabc0-4d7a-4bf8-9610-914796a5ab60

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 06 May 2016

Date accepted : 13 November 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: DK042394

Award Recipient : Randal J Kaufman

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: DK088227

Award Recipient : Randal J Kaufman

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: DK103183

Award Recipient : Randal J Kaufman

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA128814

Award Recipient : Randal J Kaufman

Funded by: FundRef http://dx.doi.org/10.13039/100000026, National Institute on Drug Abuse;

Award ID: DA09411

Award Recipient : John A Dani

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: NS21229

Award Recipient : John A Dani

Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;

Award Recipient : Peter Walter

Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;

Award ID: MH09816

Award Recipient : Mauro Costa-Mattioli

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: NS076708

Award Recipient : Mauro Costa-Mattioli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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elife-xml-version 2.5

Author impact statement Building on previous work (Huang et al., 2016), we show that translational control by p-eIF2α is a defense mechanism that prevents persistent cocaine-induced synaptic synaptic potentiation underlying compulsive drug seeking.

ScienceOpen disciplines: Life sciences

Keywords: synaptic plasticity,psychostimulant abuse,protein synthesis,ampar,drug addiciton,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: synaptic plasticity, psychostimulant abuse, protein synthesis, ampar, drug addiciton, mouse

eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons

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Abstract

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The Dynamic Brain

Most cited references 29

Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling.

Imaging dopamine's role in drug abuse and addiction.

Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.

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