Table 1.

Summary of epigenetic modifications in drug abuse.

Histone/gene	Treatment	Response	Ref.
Cocaine
c-fos	Acute	Histone H4 acetylation and increased expression at the c-fos promoter in the mouse striatum	[42,44–46]
		Build up of FosB recruited HDAC1 to the c-fos promoter to limit c-fos expression
FosB	Acute/chronic	Hypomethylation at the FosB promoter decreased MeCP2 binding and increased FosB expression in the nucleus accumbens	[43–46]
		Chronic cocaine recruited CREB-binding protein to the FosB promoter, which upregulated FosB expression in the striatum to increase cocaine sensitivity and locomotor activity
HDAC5	Chronic	Cocaine decreased HDAC5 activity in the nucleus accumbens, which increased transcription at HDAC5 target genes	[48]
CaMKIIa	Chronic	Cocaine increased H3 acetylation at the CaMKIIa gene and upregulated expression	[49]
DNMT1, Dnmt3a and Dnmt3b	Acute	Cocaine-induced expression of Dnmt3a and Dnmt3b in the nucleus accumbens	[43,59]
		Maternal cocaine exposure increased expression of DNMT1 and DNMT3a, but not 3b, at P30 in hippocampal pyramidal neurons of the offspring
MeCP2	Acute	MeCP2 phosphorylation at serine 421 in rat striatum and nucleus accumbens prevented	[50,51]
		MeCP2 from repressing transcription, thus upregulating downstream genes such as Bdnf and FosB
Cdk5	Chronic	H3 acetylation at the Cdk5 promoter in the striatum	[44]
Bdnf	Chronic	H3 acetylation at the Bdnf promoter and increased Bdnf in the hippocampus	[55–57]
		Bdnf levels did not normalize after withdrawal, indicating a role of Bdnf in drug relapse
miR-212	Chronic	Extended access to cocaine amplified CREB signaling in the striatum via Raf-1 phosphorylation, increasing sensitization of adenylyl cyclase activity	[58]
Opioids
OPRM1	Chronic	Increased OPRM1 promoter methylation associated in vitro with decreased OPRM1 mRNA content	[61,63]
	Chronic	Two OPRM1 promoter region CpG sites were hypermethylated in lymphocyte DNA of Caucasian former heroin addicts	[66]
	Chronic	DNA methylation levels at specific CpG sites of the OPRM1 promoter varied among ethnicities	[66,67]
	Chronic	Hypermethylation at seven OPRM1 CpG sites in leukocyte DNA of male opioid addicts	[68]
	Chronic	Hypermethylation at a single OPRM1-promoter CpG site in sperm of male opioid addicts	[68]
	Acute	Female adult offspring of dams treated with morphine for 10 days prior to mating had increased anxiety-like behavior, and male offspring had increased sensitivity to morphine, developing tolerance to morphine more rapidly	[70]
Alcohol
NR2B	Chronic	Methylation of CpG islands in NR2B in mouse cortical neurons increased expression	[71,73]
		Withdrawal increased NR2B gene expression with concurrent increase in H3K9 acetylation of the NR2B promoter in primary cortical neurons
		Increased expression may be due to reduced G9a, Suv39 h1 and HDAC1–3 binding to the NR2B promoter
HDAC	Acute/chronic	HDAC activity in rat amygdala decreased after acute exposure and increased with withdrawal from chronic exposure, causing increased anxiety	[73]
		Anxiety effects were reduced in rats treated with the HDAC inhibitor TSA
H3K9	Chronic	Rat hepatocytes incubated in ethanol for 1 day showed increased acetylation of H3K9 in a dose-dependent manner	[74,75]
		H3K9 acetylation was observed with chronic intragastric administration in rats, owing to an increase in p300 HDAC activity
PDYN	Chronic	Human neuroblastoma cells treated with acetaldehyde exhibited downregulated PDYN gene expression concurrent with increased H3K27 trimethylation and decreased H3K4 and H3K9 acetylation at the PDYN promoter	[76,77]
		Alcoholics had higher PDYN expression in the prefrontal cortex
HERP	Chronic	HERP gene hypermethylated and associated with increased levels of homocysteine in alcoholics	[79]
SNCA	Chronic	Hypermethylation of the SNCA gene associated with alcoholism	[82]
AVP	Chronic	Hypermethylation of the AVP gene associated with alcoholism	[83]
ANP	Chronic	Hypomethylation at the ANP promoter region observed in alcoholics	[83]
MAOA	Chronic	Methylation of the MAOA promoter associated nominally with alcohol dependence in women	[84]
NGF	Chronic	Withdrawal shown to cause an increase in NGF promoter methylation in alcohol-dependent individuals	[85]
DLK1	Chronic	Imprinted IG-DMR region hypomethylated in sperm of alcohol-dependent subjects	[86]

HDAC: Histone deacetylase; TSA: Trichostatin A.