Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine
Author(s)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.; ... Show more Show less
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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 GluR1[superscript S845] 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 GluR1[superscript WT] in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1[superscript WT] overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1[superscript WT] 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 GluR1[superscript S845A] 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 GluR1[superscript WT] or GluR1[superscript S845A] in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Journal of Neuroscience
Society for Neuroscience
Choi, K. H. et al. “Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine.” Journal of Neuroscience 31.21 (2011): 7927–7937.
Final published version