Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5

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(1-4). One such transcription factor is Delta 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 Delta FosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of Delta 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 Delta FosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.