A silent synapse-based mechanism for cocaine-induced locomotor sensitization

Travis E. Brown, Brian R. Lee, Ping Mu, Deveroux Ferguson, David Dietz, Yoshinori N. Ohnishi, Ying Lin, Anna Suska, Masago Ishikawa, Yanhua H. Huang, Haowei Shen, Peter W. Kalivas, Barbara A. Sorg, R. Suzanne Zukin, Eric J. Nestler, Yan Dong, Oliver M. Schlüüter

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation ofCREBpromotes CREB-dependent transcription ofNR2Band synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaineinduced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

Original languageEnglish (US)
Pages (from-to)8163-8174
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number22
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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    Brown, T. E., Lee, B. R., Mu, P., Ferguson, D., Dietz, D., Ohnishi, Y. N., Lin, Y., Suska, A., Ishikawa, M., Huang, Y. H., Shen, H., Kalivas, P. W., Sorg, B. A., Suzanne Zukin, R., Nestler, E. J., Dong, Y., & Schlüüter, O. M. (2011). A silent synapse-based mechanism for cocaine-induced locomotor sensitization. Journal of Neuroscience, 31(22), 8163-8174. https://doi.org/10.1523/JNEUROSCI.0016-11.2011