Fig. 4: Addictive drug abuse and epigenetic modifications.

DNA methylation and histone modifications both participate in the pathogenesis of addictive drug abuse and depression. Drug abuse and depression-related histone modifications include several types, most prominently acetylation and methylation. Histone acetylation is catalyzed by HATs and reversed by HDACs. Histone methylation is catalyzed by HMTs/KMTs. a DNA methylation. In MDD, aberrant DNA methylation of NR3C1 and FKBP5 was found. Cocaine administration significantly elevated FKBP5 during the early withdrawal phase. Early postpartum alcohol exposure led to persistent hypermethylation of the hippocampal FKBP5 promoter, disrupting HPA axis feedback and thus enhancing susceptibility to depression-like behaviors. In the prefrontal cortex of patients with alcohol use disorder, elevated NR3C1 promoter methylation levels have also been observed; b histone methylation. In addiction research, cocaine enhanced the expression of G9a (an H3K9-specific methyltransferase), leading to increased H3K9me2 in the NAc and enhanced drug reward. Similarly, the antidepressant fluoxetine alleviates depressive behaviors by promoting G9a-mediated restoration of H3K9me2. Both depression and drug addiction are associated with increased H3K4me3. METH reduced the expression of the methyltransferase Mll1 KMT2A and the demethylase Kdm5c in the NAc, leading to elevated H3K4me3 at the Oxtr and Fos promoters and strengthening drug-seeking behavior. In patients with depression—particularly in the prefrontal cortex-elevated H3K4me3 contributes to astrocytic dysfunction, exacerbating depressive symptoms and increasing suicide risk; c histone acetylation. Both addiction and depression exhibit dysregulated histone acetylation. METH exposure and stress-susceptible depressive phenotypes are characterized by reduced H3K9ac. METH and most depressive models show increased HDAC2 activity. The specific mechanisms underlying these changes require further investigation. Histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs/KMTs), major depressive disorder (MDD), FK506 binding protein 5 (FKBP5), nuclear receptor subfamily 3 group C member 1 (NR3C1), nucleus accumbens (NAc), methamphetamine (METH), mixed lineage leukemia 1 (Mll1), lysine-specific methyltransferase 2A (KMT2A), lysine-specific demethylase 5C (Kdm5c), oxytocin receptor (Oxtr). (Figure was created by Adobe Illustrator 2023).