Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.
Katherine N WrightFiona HollisFlorian DuclotAmanda M DossatCaroline E StrongT Chase FrancisRoger MercerJian FengDavid M DietzMary Kay LoboEric J NestlerMohamed KabbajPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2015)
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.
Keyphrases
- dna methylation
- prefrontal cortex
- genome wide
- drug induced
- gene expression
- transcription factor
- high glucose
- copy number
- endothelial cells
- spinal cord injury
- poor prognosis
- mental health
- signaling pathway
- tyrosine kinase
- cell proliferation
- cell free
- genome wide analysis
- high dose
- single molecule
- machine learning
- brain injury
- long non coding rna
- blood brain barrier
- big data
- white matter
- electronic health record
- cerebral ischemia
- subarachnoid hemorrhage
- combination therapy
- intimate partner violence