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

Craig T. Werner, Michael T. Stefanik, Mike Milovanovic, Aaron Caccamise, Marina Wolf

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies (“incubates”) during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneuro-somes prepared after ☓47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2β (eIF2β) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2β dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.

Original languageEnglish (US)
Pages (from-to)2683-2697
Number of pages15
JournalJournal of Neuroscience
Volume38
Issue number11
DOIs
StatePublished - Mar 14 2018
Externally publishedYes

Fingerprint

Nucleus Accumbens
Protein Biosynthesis
Cocaine
Cues
Eukaryotic Initiation Factor-2
Sirolimus
Craving
Peptide Elongation Factor 2
Anisomycin
Self Administration
Pharmaceutical Preparations
Recurrence
Injections

Keywords

  • Cocaine
  • EIF2β
  • Incubation
  • MTOR
  • NAc
  • Protein translation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Protein translation in the nucleus accumbens is dysregulated during cocaine withdrawal and required for expression of incubation of cocaine craving. / Werner, Craig T.; Stefanik, Michael T.; Milovanovic, Mike; Caccamise, Aaron; Wolf, Marina.

In: Journal of Neuroscience, Vol. 38, No. 11, 14.03.2018, p. 2683-2697.

Research output: Contribution to journalArticle

Werner, Craig T. ; Stefanik, Michael T. ; Milovanovic, Mike ; Caccamise, Aaron ; Wolf, Marina. / Protein translation in the nucleus accumbens is dysregulated during cocaine withdrawal and required for expression of incubation of cocaine craving. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 11. pp. 2683-2697.
@article{0c8116aa0ca24db88992364d2d5014b3,
title = "Protein translation in the nucleus accumbens is dysregulated during cocaine withdrawal and required for expression of incubation of cocaine craving",
abstract = "Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies (“incubates”) during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneuro-somes prepared after ☓47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2β (eIF2β) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2β dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.",
keywords = "Cocaine, EIF2β, Incubation, MTOR, NAc, Protein translation",
author = "Werner, {Craig T.} and Stefanik, {Michael T.} and Mike Milovanovic and Aaron Caccamise and Marina Wolf",
year = "2018",
month = "3",
day = "14",
doi = "10.1523/JNEUROSCI.2412-17.2018",
language = "English (US)",
volume = "38",
pages = "2683--2697",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "11",

}

TY - JOUR

T1 - Protein translation in the nucleus accumbens is dysregulated during cocaine withdrawal and required for expression of incubation of cocaine craving

AU - Werner, Craig T.

AU - Stefanik, Michael T.

AU - Milovanovic, Mike

AU - Caccamise, Aaron

AU - Wolf, Marina

PY - 2018/3/14

Y1 - 2018/3/14

N2 - Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies (“incubates”) during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneuro-somes prepared after ☓47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2β (eIF2β) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2β dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.

AB - Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies (“incubates”) during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneuro-somes prepared after ☓47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2β (eIF2β) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2β dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.

KW - Cocaine

KW - EIF2β

KW - Incubation

KW - MTOR

KW - NAc

KW - Protein translation

UR - http://www.scopus.com/inward/record.url?scp=85043754559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043754559&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2412-17.2018

DO - 10.1523/JNEUROSCI.2412-17.2018

M3 - Article

AN - SCOPUS:85043754559

VL - 38

SP - 2683

EP - 2697

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 11

ER -