Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization

Xiaoting Wang, Michael E. Cahill, Craig T. Werner, Daniel J. Christoffel, Sam A. Golden, Zhong Xie, Jessica A. Loweth, Michela Marinelli, Scott J. Russo, Peter Penzes, Marina E. Wolf

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

It is well established that behavioral sensitization to cocaine is accompanied by increased spine density and AMPA receptor (AMPAR) transmission in the nucleus accumbens (NAc), but two major questions remain unanswered. Are these adaptations mechanistically coupled? And, given that they can be dissociated from locomotor sensitization, what is their functional significance? We tested the hypothesis that the guanine-nucleotide exchange factor Kalirin-7 (Kal-7) couples cocaine-induced AMPAR and spine upregulation and that these adaptations underlie sensitization of cocaine's incentive-motivational properties-the properties that make it "wanted." Rats received eight daily injections of saline or cocaine. On withdrawal day 14, we found that Kal-7 levels and activation of its downstream effectors Rac-1 andPAKwere increased in the NAc of cocaine-sensitized rats. Furthermore,AMPARsurface expression and spine density were increased, as expected. To determine whether these changes require Kal-7, a lentiviral vector expressing Kal-7 shRNA was injected into the NAc core before cocaine exposure. Knocking down Kal-7 abolished the AMPAR and spine upregulation normally seen during cocaine withdrawal. Despite the absence of these adaptations, rats with reduced Kal-7 levels developed locomotor sensitization. However, incentive sensitization, which was assessed by how rapidly rats learned to self-administer a threshold dose of cocaine, was severely impaired. These results identify a signaling pathway coordinating AMPAR and spine upregulation during cocaine withdrawal, demonstrate that locomotor and incentive sensitization involve divergent mechanisms, and link enhanced excitatory transmission in the NAc to incentive sensitization.

Original languageEnglish (US)
Pages (from-to)11012-11022
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number27
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wang, X., Cahill, M. E., Werner, C. T., Christoffel, D. J., Golden, S. A., Xie, Z., Loweth, J. A., Marinelli, M., Russo, S. J., Penzes, P., & Wolf, M. E. (2013). Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization. Journal of Neuroscience, 33(27), 11012-11022. https://doi.org/10.1523/JNEUROSCI.1097-13.2013