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

Michael T. Stefanik, Mike Milovanovic, Craig T. Werner, John C.G. Spainhour, Marina Wolf

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalBiological Psychiatry
Volume84
Issue number3
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

Fingerprint

Self Administration
Nucleus Accumbens
Protein Biosynthesis
Cocaine
N-Methyl-D-Aspartate Receptors
Isoxazoles
Puromycin
Pharmaceutical Preparations
alpha-methyl-4-carboxyphenylglycine
Central Nervous System Diseases
Cues
Hippocampus
Proteins
Maintenance
Brain

Keywords

  • AMPA receptor
  • Incubation of cocaine craving
  • Metabolic labeling
  • Nucleus accumbens
  • Protein translation
  • Puromycin

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens. / Stefanik, Michael T.; Milovanovic, Mike; Werner, Craig T.; Spainhour, John C.G.; Wolf, Marina.

In: Biological Psychiatry, Vol. 84, No. 3, 01.08.2018, p. 223-232.

Research output: Contribution to journalArticle

Stefanik, Michael T. ; Milovanovic, Mike ; Werner, Craig T. ; Spainhour, John C.G. ; Wolf, Marina. / Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens. In: Biological Psychiatry. 2018 ; Vol. 84, No. 3. pp. 223-232.
@article{eb727a9bc803452a893733f0f30532ec,
title = "Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens",
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-na{\"i}ve NAc or after incubation. Methods: NAc tissue was obtained from drug-na{\"i}ve 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-na{\"i}ve, 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-na{\"i}ve 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.",
keywords = "AMPA receptor, Incubation of cocaine craving, Metabolic labeling, Nucleus accumbens, Protein translation, Puromycin",
author = "Stefanik, {Michael T.} and Mike Milovanovic and Werner, {Craig T.} and Spainhour, {John C.G.} and Marina Wolf",
year = "2018",
month = "8",
day = "1",
doi = "10.1016/j.biopsych.2018.02.012",
language = "English (US)",
volume = "84",
pages = "223--232",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "3",

}

TY - JOUR

T1 - Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens

AU - Stefanik, Michael T.

AU - Milovanovic, Mike

AU - Werner, Craig T.

AU - Spainhour, John C.G.

AU - Wolf, Marina

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - AMPA receptor

KW - Incubation of cocaine craving

KW - Metabolic labeling

KW - Nucleus accumbens

KW - Protein translation

KW - Puromycin

UR - http://www.scopus.com/inward/record.url?scp=85044732741&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044732741&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2018.02.012

DO - 10.1016/j.biopsych.2018.02.012

M3 - Article

VL - 84

SP - 223

EP - 232

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 3

ER -