Acute administration of cocaine to mice does not affect Cdk5 activity. It does decrease DARPP-32 phosphorylation at Thr-75 via PKA-mediated activation of PP-2A.72 Chronic administration of cocaine increases Cdk5 activity, likely through the induction of deltaFosB141 and increased transcription of Cdk5.82 Rats treated chronically with cocaine show increased Cdk5 and p35 mRNA in the dorsal striatum and NAc.82 Rats that have been chronically self-administering cocaine display higher NAc Cdk5 protein levels than control rats.142 Similarly, rats chronically treated with methamphetamine143 show increased Cdk5 activity in the ventral striatum. Chronic ethanol exposure also increases Cdk5 immunoreactivity in the rat NAc144 and enhances Cdk5 activity in frontal cortex and cerebellum.145 Mice treated chronically with cocaine82 resemble transgenic mice that overexpress p35.146 In both cases, the effects of single cocaine injections on the induction of PKA-mediated DARPP-32 phosphorylation at Thr-34 are attenuated. Thus, the effects of acute cocaine are dampened in animals exposed repeatedly to cocaine due to the increased expression and activity of Cdk5. High Cdk5 activity can also attenuate downstream activation of other cocaine-stimulated signal transduction pathways. When treated acutely with
