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

Autor: Jane R. Taylor, Akinori Nishi, James A. Bibb, Charles C. Ouimet, Zachary K. Sagawa, Angus C. Nairn, Eric J. Nestler, Per Svenningsson, Gretchen L. Snyder, Zhen Yan, Jingshan Chen, Paul Greengard
Rok vydání: 2001
Předmět:
Male
Dopamine and cAMP-Regulated Phosphoprotein 32
medicine.medical_specialty
Dopamine
media_common.quotation_subject
Mice
Transgenic
Nerve Tissue Proteins
Striatum
Neurotransmission
Biology
Medium spiny neuron
Gene Expression Regulation
Enzymologic
Rats
Sprague-Dawley
Cocaine-Related Disorders
Mice
Cocaine
Internal medicine
Roscovitine
medicine
Animals
Enzyme Inhibitors
Phosphorylation
Transcription factor
Oligonucleotide Array Sequence Analysis
media_common
Neurons
Multidisciplinary
Receptors
Dopamine D1
Addiction
Cyclin-dependent kinase 5
Brain
Cyclin-Dependent Kinase 5
Kinetin
Phosphoproteins
Corpus Striatum
Cyclin-Dependent Kinases
Rats
Endocrinology
nervous system
Purines
Dopamine receptor
Proto-Oncogene Proteins c-fos
Neuroscience
Psychomotor Performance
Signal Transduction
medicine.drug
Zdroj: Nature. 410:376-380
ISSN: 1476-4687
0028-0836
Popis: 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.
Databáze: OpenAIRE
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