Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine

Kwang Ho Choi, Scott Edwards, Danielle L. Graham, Erin B. Larson, Kimberly N. Whisler, Diana Simmons, Allyson K. Friedman, Jessica J. Walsh, Zia Rahman, Lisa M Monteggia, Amelia J Eisch, Rachael L. Neve, Eric J. Nestler, Ming Hu Han, David W Self

Research output: Contribution to journalArticle

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Abstract

Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1S845 phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1WT in rat VTA primarily infected dopamine neurons (75%) and increasedAMPAreceptor-mediated membrane rectification in these neurons with AMPAapplication. Similar GluR1WT overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1WT in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1S845A in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1WT or GluR1S845A in the adjacent substantia nigra had no effect on cocaine self administration. Together, these results suggest that dynamic regulation ofAMPAreceptors in theVTAduring cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

Original languageEnglish (US)
Pages (from-to)7927-7937
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number21
DOIs
StatePublished - May 25 2011

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Ventral Tegmental Area
AMPA Receptors
Glutamate Receptors
Cocaine
Motivation
Self Administration
Reinforcement Schedule
Reinforcement (Psychology)
Up-Regulation
Cocaine-Related Disorders
Messenger RNA
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Viral Genes
Dopaminergic Neurons
Substantia Nigra
N-Methylaspartate
Cyclic AMP-Dependent Protein Kinases
Sucrose
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine. / Choi, Kwang Ho; Edwards, Scott; Graham, Danielle L.; Larson, Erin B.; Whisler, Kimberly N.; Simmons, Diana; Friedman, Allyson K.; Walsh, Jessica J.; Rahman, Zia; Monteggia, Lisa M; Eisch, Amelia J; Neve, Rachael L.; Nestler, Eric J.; Han, Ming Hu; Self, David W.

In: Journal of Neuroscience, Vol. 31, No. 21, 25.05.2011, p. 7927-7937.

Research output: Contribution to journalArticle

Choi, KH, Edwards, S, Graham, DL, Larson, EB, Whisler, KN, Simmons, D, Friedman, AK, Walsh, JJ, Rahman, Z, Monteggia, LM, Eisch, AJ, Neve, RL, Nestler, EJ, Han, MH & Self, DW 2011, 'Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine', Journal of Neuroscience, vol. 31, no. 21, pp. 7927-7937. https://doi.org/10.1523/JNEUROSCI.6014-10.2011
Choi, Kwang Ho ; Edwards, Scott ; Graham, Danielle L. ; Larson, Erin B. ; Whisler, Kimberly N. ; Simmons, Diana ; Friedman, Allyson K. ; Walsh, Jessica J. ; Rahman, Zia ; Monteggia, Lisa M ; Eisch, Amelia J ; Neve, Rachael L. ; Nestler, Eric J. ; Han, Ming Hu ; Self, David W. / Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 21. pp. 7927-7937.
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AU - Whisler, Kimberly N.

AU - Simmons, Diana

AU - Friedman, Allyson K.

AU - Walsh, Jessica J.

AU - Rahman, Zia

AU - Monteggia, Lisa M

AU - Eisch, Amelia J

AU - Neve, Rachael L.

AU - Nestler, Eric J.

AU - Han, Ming Hu

AU - Self, David W

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N2 - Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1S845 phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1WT in rat VTA primarily infected dopamine neurons (75%) and increasedAMPAreceptor-mediated membrane rectification in these neurons with AMPAapplication. Similar GluR1WT overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1WT in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1S845A in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1WT or GluR1S845A in the adjacent substantia nigra had no effect on cocaine self administration. Together, these results suggest that dynamic regulation ofAMPAreceptors in theVTAduring cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

AB - Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1S845 phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1WT in rat VTA primarily infected dopamine neurons (75%) and increasedAMPAreceptor-mediated membrane rectification in these neurons with AMPAapplication. Similar GluR1WT overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1WT in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1S845A in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1WT or GluR1S845A in the adjacent substantia nigra had no effect on cocaine self administration. Together, these results suggest that dynamic regulation ofAMPAreceptors in theVTAduring cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

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