Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling.
Cocaine, a drug of abuse, increases synaptic dopamine levels in the striatum by blocking dopamine reuptake at axon terminals. Cyclin-dependent kinase 5 (Cdk5) and its activator p35, proteins involved in phosphorylation of substrates in postmitotic neurons, have been found to be up-regulated after chronic exposure to cocaine. To further examine the effects of Cdk5 and p35 induction on striatal dopamine signaling, we generated two independent transgenic mouse lines in which Cdk5 or p35 was overexpressed specifically in neurons. We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling. Increased Cdk5-mediated phosphorylation of dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa (DARPP-32) at Thr-75, was accompanied by decreased phosphorylation of DARPP-32 at Thr-34. Increased Cdk5-mediated phosphorylation of extracellular signal-regulated kinase kinase 1 at Thr-286 was accompanied by decreased activation of extracellular signal-regulated kinase 1/2. These effects contributed to attenuation of cocaine-induced phosphorylation of cAMP response element-binding protein as well as a lesser induction of c-fos in the striatum. These results support the idea that Cdk5 activity is involved in altered gene expression after chronic exposure to cocaine and hence impacts the long-lasting changes in neuronal function underlying cocaine addiction.
Takahashi
Satoru
S
Functional Genomics Section, Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA.
Ohshima
Toshio
T
Cho
Andrew
A
Sreenath
Taduru
T
Iadarola
Michael J
MJ
Pant
Harish C
HC
Kim
Yong
Y
Nairn
Angus C
AC
Brady
Roscoe O
RO
Greengard
Paul
P
Kulkarni
Ashok B
AB
D000818:Animals; D001921:Brain / Q000502:physiology; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D015183:Restriction Mapping; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology; D013569:Synapses / Q000502:physiology*
D012313:RNA; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D003042:Cocaine; D004298:Dopamine