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

Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine r e-uptake at axon terminals. Most dopamine-containing nerve terminals innerv ate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equ ilibrium by countering the effects of repeated drug administration(1,2). Ch ronic exposure to cocaine upregulates several transcription factors that al ter gene expression and which could mediate such compensatory neural and be havioural changes(1-4). One such transcription factor is Delta FosB, a prot ein 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 ge ne of Delta FosB by use of DNA array analysis of striatal material from ind ucible transgenic mice. Overexpression of Delta FosB, or chronic cocaine ad ministration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum pot entiated behavioural effects of repeated cocaine administration. Our result s suggest that changes in Cdk5 levels mediated by Delta FosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to a daptive changes in the brain related to cocaine addiction.