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. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes. One such transcription factor is DeltaFosB, a protein that persists in striatum long after the end of cocaine exposure. Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of DeltaFosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of DeltaFosB, 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 DeltaFosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.
Bibb
J A
JA
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA. bibbj@rockvax.rockefeller.edu
Chen
J
J
Taylor
J R
JR
Svenningsson
P
P
Nishi
A
A
Snyder
G L
GL
Yan
Z
Z
Sagawa
Z K
ZK
Ouimet
C C
CC
Nairn
A C
AC
Nestler
E J
EJ
Greengard
P
P
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007701:Kinetin; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D000077546:Roscovitine; D015398:Signal Transduction
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D011687:Purines; D017447:Receptors, Dopamine D1; D000077546:Roscovitine; C090046:olomoucine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D003042:Cocaine; D007701:Kinetin; D004298:Dopamine