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 journalArticle

70 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)12967-12976
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number47
DOIs
StatePublished - Nov 21 2007

Fingerprint

Cyclin-Dependent Kinase 5
Corpus Striatum
Reward
Cocaine
Motivation
Neurons
Nucleus Accumbens
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Knockout Mice
Reinforcement Schedule
Dependovirus
Psychotropic Drugs
Street Drugs
Prosencephalon
Synaptic Transmission

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Benavides, D. R., Quinn, J. J., Zhong, P., Hawasli, A. H., DiLeone, R. J., Kansy, J. W., ... Bibb, J. A. (2007). Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. Journal of Neuroscience, 27(47), 12967-12976. https://doi.org/10.1523/JNEUROSCI.4061-07.2007

Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. / Benavides, David R.; Quinn, Jennifer J.; Zhong, Ping; Hawasli, Ammar H.; DiLeone, Ralph J.; Kansy, Janice W.; Olausson, Peter; Yan, Zhen; Taylor, Jane R.; Bibb, James A.

In: Journal of Neuroscience, Vol. 27, No. 47, 21.11.2007, p. 12967-12976.

Research output: Contribution to journalArticle

Benavides, DR, Quinn, JJ, Zhong, P, Hawasli, AH, DiLeone, RJ, Kansy, JW, Olausson, P, Yan, Z, Taylor, JR & Bibb, JA 2007, 'Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability', Journal of Neuroscience, vol. 27, no. 47, pp. 12967-12976. https://doi.org/10.1523/JNEUROSCI.4061-07.2007
Benavides DR, Quinn JJ, Zhong P, Hawasli AH, DiLeone RJ, Kansy JW et al. Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. Journal of Neuroscience. 2007 Nov 21;27(47):12967-12976. https://doi.org/10.1523/JNEUROSCI.4061-07.2007
Benavides, David R. ; Quinn, Jennifer J. ; Zhong, Ping ; Hawasli, Ammar H. ; DiLeone, Ralph J. ; Kansy, Janice W. ; Olausson, Peter ; Yan, Zhen ; Taylor, Jane R. ; Bibb, James A. / Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 47. pp. 12967-12976.
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