Repeated cocaine injections that result in locomotor sensitization increase Cdk5 levels and Cdk5-mediated DARPP-32 phosphorylation, and decrease PKA-mediated DARPP-32 phosphorylation in the rat dorsal striatum and NAc.149 Pretreatment with the Cdk5 inhibitors roscovitine or olomoucine enhances the development of cocaine-induced locomotor sensitization in mice82 and rats.150 In contrast, heterozygous Cdk5 null mice show reduced morphine-induced locomotor sensitization.151 However, conditional Cdk5 knockout mice, in which forebrain deletion of Cdk5 is achieved in the adult through αCaMKII promoter-driven Cre recombinase, show enhanced cocaine-induced locomotor sensitization.152 Therefore, induction of Cdk5 activity by repeated exposure to cocaine appears to act as an adaptive feedback response that decreases the sensitizing effects of the drug, whereas for morphine Cdk5 appears to facilitate drug sensitization. The mechanisms by which Cdk5 regulates sensitization are not understood but may involve both its kinase activity as well as its recently described kinase independent role in regulating glutamate receptor degradation.153
