Constitutive knockout of Kalirin-7 leads to increased rates of cocaine self-administration

Drew D. Kiraly, Natali E. Nemirovsky, Taylor P. LaRese, Seven E. Tomek, Stephanie L. Yahn, Michael Olive, Betty A. Eipper, Richard E. Mains

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Kalirin-7 (Kal7) is a Rho-guanine nucleotide exchange factor that is localized in neuronal postsynaptic densities. Kal7 interacts with the NR2B subunit of the NMDA receptor and regulates aspects of dendritic spine dynamics both in vitro and in vivo. Chronic treatment with cocaine increases dendritic spine density in the nucleus accumbens (NAc) of rodents and primates. Kal7 mRNA and protein are upregulated in the NAc following cocaine treatment, and the presence of Kal7 is necessary for the normal proliferation of dendritic spines following cocaine use. Mice that constitutively lack Kal7 [Kalirin-7 knockout mice (Kal7KO)] demonstrate increased locomotor sensitization to cocaine and a decreased place preference for cocaine. Here, using an intravenous cocaine self-administration paradigm, Kal7KO mice exhibit increased administration of cocaine at lower doses as compared with wild-type (Wt) mice. Analyses of mRNA transcript levels from the NAc of mice that self-administered saline or cocaine reveal that larger splice variants of the Kalrn gene are increased by cocaine more dramatically in Kal7KO mice than in Wt mice. Additionally, transcripts encoding the NR2B subunit of the NMDA receptor increased in Wt mice that self-administered cocaine but were unchanged in similarly experienced Kal7KO mice. These findings suggest that Kal7 participates in the reinforcing effects of cocaine, and that Kal7 and cocaine interact to alter the expression of genes related to critical glutamatergic signaling pathways in the NAc.

Original languageEnglish (US)
Pages (from-to)582-590
Number of pages9
JournalMolecular Pharmacology
Volume84
Issue number4
DOIs
StatePublished - Oct 1 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Kiraly, D. D., Nemirovsky, N. E., LaRese, T. P., Tomek, S. E., Yahn, S. L., Olive, M., Eipper, B. A., & Mains, R. E. (2013). Constitutive knockout of Kalirin-7 leads to increased rates of cocaine self-administration. Molecular Pharmacology, 84(4), 582-590. https://doi.org/10.1124/mol.113.087106