Elsevier

Biological Psychiatry

Volume 84, Issue 3, 1 August 2018, Pages 223-232
Biological Psychiatry

Archival Report
Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens

https://doi.org/10.1016/j.biopsych.2018.02.012Get rights and content

Abstract

Background

Cue-induced cocaine craving incubates during abstinence from cocaine self-administration. Expression of incubation ultimately depends on elevation of homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in the nucleus accumbens (NAc). This adaptation requires ongoing protein translation for its maintenance. Aberrant translation is implicated in central nervous system diseases, but nothing is known about glutamatergic regulation of translation in the drug-naïve NAc or after incubation.

Methods

NAc tissue was obtained from drug-naïve rats and from rats after 1 or >40 days of abstinence from extended-access cocaine or saline self-administration. Newly translated proteins were labeled using 35S-Met/Cys or puromycin. We compared basal overall translation and its regulation by metabotropic glutamate receptor 1 (mGlu1), mGlu5, and N-methyl-D-aspartate receptors (NMDARs) in drug-naïve, saline control, and cocaine rats, and we compared GluA1 and GluA2 translation by immunoprecipitating puromycin-labeled proteins.

Results

In all groups, overall translation was unaltered by mGlu1 blockade (LY367385) but increased by mGlu5 blockade (MTEP). NMDAR blockade (AVP) increased overall translation in drug-naïve and saline control rats but not in cocaine/late withdrawal rats. Cocaine/late withdrawal rats exhibited greater translation of GluA1 (but not GluA2), which was not further affected by NMDAR blockade.

Conclusions

Our results suggest that increased GluA1 translation contributes to the elevated homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels in the NAc that mediate incubation. Additional contributions to incubation-related plasticity may result from loss of the braking influence on translation normally exerted by NMDARs. Apart from elucidating incubation-related adaptations, we found a suppressive effect of mGlu5 on NAc translation regardless of drug exposure, which is opposite to results obtained in the hippocampus and points to heterogeneity of translational regulation between brain regions.

Section snippets

Subjects and Drug Self-administration

All procedures were approved by the Rosalind Franklin University Institutional Animal Care and Use Committee in accordance with the U.S. Public Health Service Guide for Care and Use of Laboratory Animals. Adult male Sprague Dawley rats underwent extended-access cocaine or saline self-administration (6 hours/day), as described previously (12) and in the Supplement.

Metabolic Labeling

Procedures were adapted from well-established protocols 22, 24 (see Supplemental Figure S1 for timeline). Rats were decapitated, and

Measuring Protein Translation in the NAc

To confirm that 35S-Met/Cys incorporates into newly translated proteins in the NAc, we preexposed tissue from naïve animals to the translation inhibitor cycloheximide (60 μM) for 30 minutes before moving the tissue into a chamber containing cycloheximide and 35S-Met/Cys for an additional 60 minutes. We then processed tissue for sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)/autoradiography. Figure 1A, B shows incorporation of 35S-Met/Cys into newly synthesized proteins

Discussion

This study is the first to characterize regulation of protein translation in the NAc by glutamate transmission. In addition, we tested the hypothesis that this regulation was altered after incubation of cocaine craving. Our results reveal mGlu5 and NMDAR regulation of translation under control conditions, loss of NMDAR regulation of translation after incubation, and increased GluA1 translation after incubation.

We suggest that our results primarily reflect translation in MSNs given that these

Acknowledgments and Disclosures

This research was supported by United States Public Health Service Grant DA015835 (to MEW), postdoctoral National Research Service Award DA040414 (to MTS), and predoctoral National Research Service Award DA036950 (to CTW).

We thank Emily Osterweil for generously sharing protocols and otherwise advising us on the metabolic labeling experiments and thank Xuan (Anna) Li for helping with the design of quantitative polymerase chain reaction experiments.

The authors report no biomedical financial

References (79)

  • M. Costa-Mattioli et al.

    Translational control of long-lasting synaptic plasticity and memory

    Neuron

    (2009)
  • J.A. Loweth et al.

    Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving

    Neuropharmacology

    (2014)
  • M.W. Waung et al.

    Protein translation in synaptic plasticity: mGluR-LTD, fragile X

    Curr Opin Neurobiol

    (2009)
  • B.P. Clark et al.

    (+)-2-Methyl-4-caboxyphenylglycine (LY367385) selectively antagonises metabotropic glutamate mGluR1 receptors

    Bioorg Med Chem Lett

    (1997)
  • C.R. Ferrario et al.

    Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca2+-permeable AMPA receptors during the incubation of cocaine craving

    Neuropharmacology

    (2011)
  • S.R. Starck et al.

    A general approach to detect protein expression in vivo using fluorescent puromycin conjugates

    Chem Biol

    (2004)
  • K.K. Szumlinski et al.

    Homers regulate drug-induced neuroplasticity: Implications for addiction

    Biochem Pharmacol

    (2008)
  • L.J. Stoppel et al.

    Beta-arrestin2 couples metabotropic glutamate receptor 5 to neuronal protein synthesis and is a potential target to treat fragile X

    Cell Rep

    (2017)
  • M.K. Bird et al.

    The mGlu5 receptor regulates extinction of cocaine-driven behaviours

    Drug Alcohol Depend

    (2014)
  • E. Taha et al.

    The role of eEF2 pathway in learning and synaptic plasticity

    Neurobiol Learn Mem

    (2013)
  • A.R. Childress et al.

    Limbic activation during cue-induced cocaine craving

    Am J Psychiatry

    (1999)
  • M.A. Parvaz et al.

    Abstinence reverses EEG-indexed attention bias between drug-related and pleasant stimuli in cocaine-addicted individuals

    J Psychiatry Neurosci

    (2017)
  • M.E. Wolf

    Synaptic mechanisms underlying persistent cocaine craving

    Nat Rev Neurosci

    (2016)
  • C.M. Reichel et al.

    Forced abstinence model of relapse to study pharmacological treatments of substance use disorder

    Curr Drug Abuse Rev

    (2009)
  • P. Li et al.

    Incubation of alcohol craving during abstinence in patients with alcohol dependence

    Addict Biol

    (2015)
  • G. Wang et al.

    Effects of length of abstinence on decision-making and craving in methamphetamine abusers

    PLoS One

    (2013)
  • J.E. McCutcheon et al.

    Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism

    J Neurosci

    (2011)
  • J.A. Loweth et al.

    Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving

    Nat Neurosci

    (2014)
  • A.F. Scheyer et al.

    A protein synthesis-dependent mechanism sustains calcium-permeable AMPA receptor transmission in nucleus accumbens synapses during withdrawal from cocaine self-administration

    J Neurosci

    (2014)
  • C.T. Werner et al.

    Protein translation in the nucleus accumbens is dysregulated during cocaine withdrawal and required for expression of incubation of cocaine craving

    J Neurosci

    (2018)
  • M.A. Sutton et al.

    Regulation of dendritic protein synthesis by miniature synaptic events

    Science

    (2004)
  • A.E. Autry et al.

    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

    Nature

    (2011)
  • E.T. Kavalali et al.

    Synaptic mechanisms underlying rapid antidepressant action of ketamine

    Am J Psychiatry

    (2012)
  • N. Li et al.

    mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists

    Science

    (2010)
  • E.K. Osterweil et al.

    Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome

    J Neurosci

    (2010)
  • A.L. Bhakar et al.

    The pathophysiology of fragile X (and what it teaches us about synapses)

    Annu Rev Neurosci

    (2012)
  • J.D. Richter et al.

    Dysregulation and restoration of translational homeostasis in fragile X syndrome

    Nat Rev Neurosci

    (2015)
  • B.A. Sorg et al.

    Application of a protein synthesis inhibitor into the ventral tegmental area, but not the nucleus accumbens, prevents behavioral sensitization to cocaine

    Synapse

    (1995)
  • M. Mameli et al.

    Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area

    Science

    (2007)
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