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Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

Singer, Bryan F.; Neugebauer, Nichole M.; Forneris, Justin; Rodvelt, Kelli R.; Li, Dongdong; Bubula, Nancy and Vezina, Paul (2014). Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens. Neuropharmacology, 85 pp. 243–252.

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Intermittent systemic exposure to psychostimulants leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine–nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying the formation of conditioned associations. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density normally observed in this site following repeated cocaine. Mice lacking the Kal7 gene display similar effects. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5 μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threonine–alanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.

Item Type: Journal Item
Copyright Holders: 2014 Elsevier
ISSN: 1873-7064
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetT32 DA07255National Institutes of Health (NIH)
Not SetF31 DA030021-01A1National Institutes of Health (NIH)
Not SetNot SetChicago Biomedical Consortium with support from The Searle 250 B.F. Singer et al. / Neuropharmacology 85 (2014) 243e252 Funds at The Chicago Community Trust
Keywords: Conditioning; Dendritic spines; Psychostimulants; Learning; Memory; Roscovitine; Sensitization
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 50832
Depositing User: Bryan Singer
Date Deposited: 07 Sep 2017 09:40
Last Modified: 09 Dec 2018 13:41
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