title: CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat.
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.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.forename: Margarit
authors.initials: M
authors.lastname: Chiflikyan
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCoy
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Jayanthi
authors.forename: Cynthia
authors.initials: C
authors.lastname: Quintero
authors.forename: Christie
authors.initials: C
authors.lastname: Brannock
authors.forename: Chanel
authors.initials: C
authors.lastname: Barnes
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Adair
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Firas H
authors.initials: FH
authors.lastname: Kobeissy
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gold
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000009:adverse effects; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000009:adverse effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism; D019966:Substance-Related Disorders / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid; D050882:CREB-Binding Protein; D004298:Dopamine
keywords: BDNF; Dorsal striatum; Methamphetamine; Self-administration; pCREB; ΔFosB