Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability

David R. Benavides, Jennifer J. Quinn, Ping Zhong, Ammar H. Hawasli, Ralph J. DiLeone, Janice W. Kansy, Peter Olausson, Zhen Yan, Jane R. Taylor, James A. Bibb

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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 αCaMKII 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.

Original languageEnglish
Pages (from-to)12967-12976
Number of pages10
JournalJournal of Neuroscience
Issue number47
StatePublished - Nov 21 2007


  • Cdk5
  • Cocaine
  • Dopamine
  • Excitability
  • Nucleus accumbens
  • Reward


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