Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition

Jessica A. Loweth, Dongdong Li, James J. Cortright, Georgia Wilke, Okunola Jeyifous, Rachael L. Neve, K. Ulrich Bayer, Paul Vezina

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Amphetamine exposure transiently increases Ca2+/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.

Original languageEnglish (US)
Pages (from-to)1411-1416
Number of pages6
JournalJournal of Neuroscience
Volume33
Issue number4
DOIs
StatePublished - Jan 23 2013

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Loweth, J. A., Li, D., Cortright, J. J., Wilke, G., Jeyifous, O., Neve, R. L., Bayer, K. U., & Vezina, P. (2013). Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition. Journal of Neuroscience, 33(4), 1411-1416. https://doi.org/10.1523/JNEUROSCI.4386-13.2013