TY - JOUR T1 - Constitutive Knockout of Kalirin-7 Leads to Increased Rates of Cocaine Self-Administration JF - Molecular Pharmacology JO - Mol Pharmacol SP - 582 LP - 590 DO - 10.1124/mol.113.087106 VL - 84 IS - 4 AU - Drew D. Kiraly AU - Natali E. Nemirovsky AU - Taylor P. LaRese AU - Seven E. Tomek AU - Stephanie L. Yahn AU - M. Foster Olive AU - Betty A. Eipper AU - Richard E. Mains Y1 - 2013/10/01 UR - http://molpharm.aspetjournals.org/content/84/4/582.abstract N2 - 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. ER -