title: Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.
abstract: Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Wright
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306, Federal Polytechnic School of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Fiona
authors.identifier: http://orcid.org/0000-0001-6559-5736
authors.initials: F
authors.lastname: Hollis
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306.
authors.forename: Florian
authors.identifier: http://orcid.org/0000-0003-0121-5807
authors.initials: F
authors.lastname: Duclot
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Dossat
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306.
authors.forename: Caroline E
authors.identifier: http://orcid.org/0000-0001-6884-9228
authors.initials: CE
authors.lastname: Strong
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: T Chase
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306.
authors.forename: Roger
authors.initials: R
authors.lastname: Mercer
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Jian
authors.identifier: http://orcid.org/0000-0002-1177-9377
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York 14214.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0002-6927-9236
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306, mohamed.kabbaj@med.fsu.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kabbaj
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D004326:Drinking / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D005108:Extinction, Psychological; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
chemical_list: C000717967:DNMT3A protein, human; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D013549:Sweetening Agents; D013395:Sucrose; D000090205:DNA Methyltransferase 3A; D003042:Cocaine
keywords: addiction; c-Fos; cocaine; epigenetics; methionine