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.

Pilot clinical observations between food and drug seeking derived from fifty cases attending an eating disorder clinic

“…Though initially thought to determine the setting of hedonic tone, the functions of dopaminergic circuitry are now understood to be more intricate, coding for attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, along with dopaminergic gene polymorphisms and additional neurotransmitter genetic variants, may have an aggregate effect on the susceptibility to both food and drug addictions involving epigenetic effects (Wright et al., 2015). Recently, Badgaiyan, Sinha, Sajjad, and Wack (2015) clearly showed that dopaminergic tone at rest is reduced in attention-deficit/hyperactivity disorder.…”

Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

“…), immediately before being placed in the operant conditioning chambers for the drug-primed reinstatement sessions. This dose of ketamine equates to the therapeutic range previously used to assess antidepressant-like effects of ketamine (Carrier and Kabbaj 2013), and the dose of cocaine has been used previously to trigger cocaine-seeking behaviors after daily self-administration and extinction (Wright et al 2015). …”

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…All METH-trained rats significantly escalated their intake of the drug per session during the first 16 days and then maintained their intake for the remainder of the training session (Figure 1b). The repeated measures mixed analysis of variance for rewards earned included the between-subject factor group (control (CT), shocksensitive (SS), shock-resistant (SR)) and the within-subject factor of day (training days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. This analysis showed a significant effect of day × group (F (38, 608) = 18.4, P o0.001).…”

“…[1][2][3] Behavioral phenomena observed during drug SA are regulated by a diversity of interconnected but distinct brain regions that include the nucleus accumbens (NAc) and dorsal striatum, among others. [4][5][6] The NAc is an important link in the circuit of addiction because it connects to brain regions that subsume positive memory 7 and decision making, 8 two cognitive processes that regulate drug-taking behaviors in rodents and humans.…”