1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
2. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA
3. Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
4. Program in Neuroscience, Florida State University, Tallahassee, Florida 32306, USA
5. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
6. Present address: Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.

Correspondence to: James A. Bibb¹ Correspondence and requests for materials should be addressed to J.A.B. (e-mail: Email: bibbj@rockvax.rockefeller.edu).

Abstract

Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine re-uptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration^{1, 2}. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes^{1, 2, 3, 4}. One such transcription factor is FosB, a protein that persists in striatum long after the end of cocaine exposure^{3, 5}. Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of FosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of FosB, or chronic cocaine administration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioural effects of repeated cocaine administration. Our results suggest that changes in Cdk5 levels mediated by FosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.