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Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.

Title: Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.
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Name(s): Wright, Katherine N, author
Hollis, Fiona, author
Duclot, Florian, author
Dossat, Amanda M, author
Strong, Caroline E, author
Francis, T Chase, author
Mercer, Roger, author
Feng, Jian, author
Dietz, David M, author
Lobo, Mary Kay, author
Nestler, Eric J, author
Kabbaj, Mohamed, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2015-06-10
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_26063926 (IID), 10.1523/JNEUROSCI.5227-14.2015 (DOI), PMC4461693 (PMCID), 26063926 (RID), 26063926 (EID), 35/23/8948 (PII)
Keywords: Addiction, C-Fos, Cocaine, Epigenetics, Methionine
Grant Number: R01 DA037257, R01MH099085, R01MH087583, R01DA037257, P01DA008227, P01 DA008227, R01 MH087583, R01 MH099085
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461693.
Subject(s): Animals
Body Weight/drug effects
Brain/drug effects
Brain/metabolism
Cocaine/adverse effects
Cocaine-Related Disorders/etiology
Cocaine-Related Disorders/physiopathology
Conditioning, Operant/drug effects
DNA Methylation/drug effects
Disease Models, Animal
Dopamine Uptake Inhibitors/adverse effects
Drinking/drug effects
Drug-Seeking Behavior/drug effects
Eating/drug effects
Extinction, Psychological
Male
Proto-Oncogene Proteins c-fos/genetics
Proto-Oncogene Proteins c-fos/metabolism
Rats
Rats, Sprague-Dawley
Reinforcement (Psychology)
Self Administration
Sucrose/administration & dosage
Sweetening Agents/administration & dosage
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26063926
Owner Institution: FSU
Is Part Of: The Journal of neuroscience : the official journal of the Society for Neuroscience.
1529-2401
Issue: iss. 23, vol. 35

Choose the citation style.
Wright, K. N., Hollis, F., Duclot, F., Dossat, A. M., Strong, C. E., Francis, T. C., … Kabbaj, M. (2015). Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26063926