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CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2013 Oct; Vol. 58, pp. 132-43. Date of Electronic Publication: 2013 May 30. - Publication Year :
- 2013
-
Abstract
- Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in ΔFosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.<br /> (Published by Elsevier Inc.)
- Subjects :
- 3,4-Dihydroxyphenylacetic Acid metabolism
Animals
Central Nervous System Stimulants adverse effects
Conditioning, Operant drug effects
Conditioning, Operant physiology
Corpus Striatum drug effects
Disease Models, Animal
Dopamine metabolism
Gene Expression Profiling
Gene Expression Regulation physiology
Hydroxyindoleacetic Acid metabolism
Male
Methamphetamine adverse effects
Phosphorylation drug effects
Rats
Rats, Sprague-Dawley
Receptors, Dopamine metabolism
Self Administration
Serotonin metabolism
Substance-Related Disorders etiology
Substance-Related Disorders physiopathology
Time Factors
CREB-Binding Protein metabolism
Central Nervous System Stimulants administration & dosage
Corpus Striatum metabolism
Gene Expression Regulation drug effects
Methamphetamine administration & dosage
Substance-Related Disorders pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 58
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 23726845
- Full Text :
- https://doi.org/10.1016/j.nbd.2013.05.009