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

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.

Sex differences in the antidepressant-like effects of ketamine.

Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl D-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.

Testosterone and imipramine have antidepressant effects in socially isolated male but not female rats.

RATIONALE: Affective disorders are twice as likely to occur in women as they are in men suggesting a critical role for gonadal hormones in their etiology. In particular, testosterone has been shown to have protective effects in men. OBJECTIVE: To investigate antidepressant effects and interactions between testosterone and imipramine in socially isolated male and female rats. METHODS: A chronic social isolation model was used to induce an anxiety and depressive-like state in adult gonadectomized (Gnx) male and ovariectomized (Ovx) female rats receiving chronic testosterone and imipramine treatments. Their anxiety and depression-like behaviors were examined using the light-dark box, elevated plus maze, open field, sucrose preference and novelty induced hypophagia tests. RESULTS: In socially isolated rats, the anxiolytic and antidepressant effects of testosterone and imipramine were limited to male rats. Additionally, testosterone enhanced the neurogenic effect of imipramine on hippocampal cell proliferation in male rats. Although female rats exhibited signs of anxiety and depressive-like behaviors following social isolation, testosterone and/or imipramine administration had no anxiolytic or antidepressant effects in Ovx females. CONCLUSIONS: Testosterone and imipramine had anxiolytic and antidepressant effects in socially isolated male, but not female rats. Testosterone enhanced the effect of imipramine on cell proliferation in the hippocampus of male rats.