Table 3. Histone modifying enzymes mediate drug-elicited behaviors.

Histone Acetylation
Histone Acetyl Transfrases (HATs)	Region	Drug	Expression changes	Time of Exposure	Inhibition / Knockout	Behavioral Effect of Inhibition	Activation / Overexpression	Behavioral Effect of Overexpression	Refs.
CBP	NAc	Cocaine		Pre-treatment	viral mediated	locomotor sensitization CPP acquisition			25

Histone Deacetylases (HDACs)	Region	Drug	Expression changes	Time of Exposure	Inhibition / Knockout	Behavioral Effect of Inhibition	Activation / Overexpression	Behavioral Effect of Overexpression	Refs.
Class I
HDAC 1	NAc	Cocaine		Pre-treatment	viral mediated / pharmacological	locomotor sensitization			23
		Meth	protein						18
HDAC 2	NAc	Cocaine		Pre-treatment	viral mediated	locomotor sensitization			23
		Meth	protein						18
	VTA	Ethanol	protein						19
HDAC 3	NAc	Cocaine		Pre-treatment Pre-treatment	viral mediated viral mediated	locomotor sensitization CPP acquisition			23 24
	Systemic	Cocaine		Concurrent	pharmacological (1- 4 doses)	CPP extinction CPP reinstatement			29
Class IIA
HDAC 4	NAc	Cocaine	mRNA	Pre-treatment			viral mediated	drug motivation CPP acquisition	17, 13, 24
HDAC 5	NAc	Cocaine	mRNA mRNA	Pre-treatment	knockout organism wide	CPP	viral mediated	CPP acquisition	27, 24
HDAC 9	NAc	Cocaine		Pre-treatment			viral mediated	CPP acquisition	27
Class IIB
HDAC 10	Striatum	Ethanol	mRNA						15
Class III
Sirtuin 1	NAc	Cocaine	mRNA & protein	Pre-treatment	viral mediated	CPP acquisition	viral mediated	CPP acquisition & locomotor sentization	16, 30
		Morphine	mRNA & protein						30
Sirtuin 2	NAc	Cocaine	mRNA & protein	Pre-treatment			viral mediated	CPP acquisition	16, 30
Class IV
HDAC 11	Striatum	Ethanol	mRNA						15

General HDAC Inhibitors/Agonists	Region	Drug		Time of Exposure	# of doses HDACi	Behavioral Effect	# of doses agonist	Behavioral Effect	Refs.
TSA	NAc	Morphine		Pre-treatment	3	hyperactivity			44
		Heroin		Concurrent	5	CPP acquisition			41
	NAc shell	Cocaine		Post-Treatment, microinjection	5	dose response curve break point			17
	BLA	Morphine			~30	CPP acquisition CPP extinction CPP reinstatement			8
	Systemic	Cocaine		Concurrent	2 7	CPP acuisition break-point self-administration			13 45
VPA	NAc	Amphet		Pre-treatment	7	locomotor sensitization			46
	Systemic	Amphet		Concurrent	8 6	locomotor sensitization locomotor sensitization			14, 12 12
NaB	Systemic	Cocaine		Concurrent	1 2 10 1 4 7	CPP acquisition CPP extinction locomotor sensitization locomotor sensitization self-administration CPP extinction CPP reinstatement CPP extinction CPP reinstatement			47 13 48 49 47 50
Sirtinol	NAc	Cocaine		Pre-treatment, osmotic mini pump	~10	CPP acquisition self-administration			16
Resveratrol	Systemic	Cocaine		Concurrent			4	CPP acquisition	16

Histone Methylation
Methyltransferases (HMTs)	Region	Drug	Expression changes	Time of Exposure	Inhibition / Knockout	Behavioral Effect			Refs.
G9a	NAc	Cocaine/ Morphine	mRNA	Pre-treatment	viral mediated / pharmacological	CPP acquisition			33, 35
GLP	NAc	Cocaine/ Morphine	mRNA	Pre-treatment	viral mediated				33, 35
MLL1	NAc	Meth	mRNA in CPP mRNA in HC	Pre-treatment	viral mediated	CPP acquisition			36

Histone Demethylases (HDMs)	Region	Drug	Expression changes	Time of Exposure	Inhibition / Knockout	Behavioral Effect			Refs.
KDM5c	NAc	Meth	mRNA	Pre-treatment	viral mediated	CPP consolidation			36

“Writers” and “Erasers” of histone modifications mediate behavioral responses to drugs of abuse. The expression changes, brain region, drug of abuse, timing of exposure, type of manipulation, and behavioral outcome are listed for each enzyme. Only those enzymes with available information are included. Pre-treatment indicates that the manipulation occurred at least 24 hrs before exposure to drug of abuse. Concurrent indicates that the manipulation occurred between 60 and 0 min before exposure to drug. Post-treatment indicates that the manipulation occurred after exposure to drug of abuse. Arrows indicate an increase (yellow), decrease (blue) or no effect (grey). Abbreviations: Amphet – amphetamine; BLA – basolateral amygdala; CBP – CREB-binding protein; CPP – conditioned place preference; G9a – euchromatic histone-lysine N-methyltransferase 2; GLP – G9a-like protein; HC – home cage; KDM5c – lysine (K)-specific demetylase 5C; Meth – methamphetamine; MLL1 – myeloid/lymphoid mixed lineage leukemia I; NAb – sodium butyrate; NAc – nucleus accumbens; TSA – trichostatin A; VPA – valproic acid; VTA – ventral tegmental area.