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The Journal of Neuroscience, November 21, 2007, 27(47):12967-12976; doi:10.1523/JNEUROSCI.4061-07.2007

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Behavioral/Systems/Cognitive
Cdk5 Modulates Cocaine Reward, Motivation, and Striatal Neuron Excitability

David R. Benavides,¹ Jennifer J. Quinn,^2 * Ping Zhong,^3 * Ammar H. Hawasli,¹ Ralph J. DiLeone,^1,2 Janice W. Kansy,¹ Peter Olausson,² Zhen Yan,³ Jane R. Taylor,² and James A. Bibb¹

¹Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, ²Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, and ³Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, New York 14214

Correspondence should be addressed to Dr. James A. Bibb, Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, NC5.410, Dallas, TX 75390-9070. Email: james.bibb{at}utsouthwestern.edu

Cyclin-dependent kinase 5 (Cdk5) regulates dopamine neurotransmission and has been suggested to serve as a homeostatic target of chronic psychostimulant exposure. To study the role of Cdk5 in the modulation of the cellular and behavioral effects of psychoactive drugs of abuse, we developed Cre/loxP conditional knock-out systems that allow temporal and spatial control of Cdk5 expression in the adult brain. Here, we report the generation of Cdk5 conditional knock-out (cKO) mice using the CaMKII promoter-driven Cre transgenic line (CaMKII-Cre). In this model system, loss of Cdk5 in the adult forebrain increased the psychomotor-activating effects of cocaine. Additionally, these CaMKII-Cre Cdk5 cKO mice show enhanced incentive motivation for food as assessed by instrumental responding on a progressive ratio schedule of reinforcement. Behavioral changes were accompanied by increased excitability of medium spiny neurons in the nucleus accumbens (NAc) in Cdk5 cKO mice. To study NAc-specific effects of Cdk5, another model system was used in which recombinant adeno-associated viruses expressing Cre recombinase caused restricted loss of Cdk5 in NAc neurons. Targeted knock-out of Cdk5 in the NAc facilitated cocaine-induced locomotor sensitization and conditioned place preference for cocaine. These results suggest that Cdk5 acts as a negative regulator of neuronal excitability in the NAc and that Cdk5 may govern the behavioral effects of cocaine and motivation for reinforcement.

Key words: cocaine; Cdk5; reward; dopamine; nucleus accumbens; excitability

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Received July 6, 2007; revised Oct. 4, 2007; accepted Oct. 5, 2007.

Correspondence should be addressed to Dr. James A. Bibb, Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, NC5.410, Dallas, TX 75390-9070. Email: james.bibb{at}utsouthwestern.edu

This article has been cited by other articles:

				D. A. Price, A. Sorkin, and N. R. Zahniser Cyclin-Dependent Kinase 5 Inhibitors: Inhibition of Dopamine Transporter Activity Mol. Pharmacol., October 1, 2009; 76(4): 812 - 823. [Abstract] [Full Text] [PDF]

				S. Kourrich and M. J. Thomas Similar Neurons, Opposite Adaptations: Psychostimulant Experience Differentially Alters Firing Properties in Accumbens Core versus Shell J. Neurosci., September 30, 2009; 29(39): 12275 - 12283. [Abstract] [Full Text] [PDF]

				D. C. Lagace, D. R. Benavides, J. W. Kansy, M. Mapelli, P. Greengard, J. A. Bibb, and A. J. Eisch Cdk5 is essential for adult hippocampal neurogenesis PNAS, November 25, 2008; 105(47): 18567 - 18571. [Abstract] [Full Text] [PDF]

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