Table 5.

The epigenetic theorem.

Reference	Topic	Comment
[122]	Dual mechanisms of opiate dependence in the locus coeruleus	Together, data from VTA and LC illustrate the complex and important changes in synaptic, cellular, and structural plasticity that mediate the lasting effects of opiate drugs on the brain's catecholamine neurons and other neuronal types in these regions, which in turn influence drug reward and dependence.
[123]	The common intracellular actions of chronic morphine and cocaine in dopaminergic brain reward regions	Lesions in the VTA disrupt self-administration of cocaine and opioids due to impairment of dopaminergic signaling
[124]	neurotrophic factors influence morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system	Increase in tyrosine hydroxylase in the VTA following chronic morphine and chronic cocaine treatments has been shown in previous research. Chronic morphine treatment also increases levels of glial fibrillary acidic protein in this brain region. Brain-derived neurotrophic factor, which by itself tended to decrease tyrosine hydroxylase levels in the VTA, prevented the characteristic increase in tyrosine hydroxylase following morphine and cocaine exposure and reversed the increase in rats pretreated with morphine.
[125]	Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus.	Increased NMDAR1 subunit levels in the hippocampus after chronic ethanol exposure may represent an important neurochemical substrate for some of the features associated with ethanol dependence and withdrawal.
[126]	A persistent decrease in adenylate cyclase is a novel action of morphine in the rat locus coeruleus	A persistent decrease in adenylate cyclase occurred in a dose-dependent manner mediated through the actions of morphine at opiate receptors. Naltrexone, a long-acting opiate receptor antagonist was administered in vivo concomitantly and prevented the inhibition.
[127]	Chronic buprenorphine treatment attenuates cocaine conditioned place preference.	Buprenorphine (BUP), a mixed opioid agonist-antagonist, was shown to suppresses cocaine self-administration in monkeys and reduce cocaine use in humans. This study found that BUP reduces the ability of cocaine to condition a place preference in rats.
[128]	The expression of GABAA receptor alpha 1 and alpha 5 subunits in the VTA and hippocampus are regulated by chronic ethanol administration	Based on these data the effects of chronic ethanol administration on the GABAA receptor subunit expression in the hippocampus and VTA may play a role in craving and other detrimental cognitive effects of alcohol.
[129]	Chronic cocaine effects regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens	Levels of Fos-like c-fos and c-jun mRNA immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels. Meanwhile in animals treated chronically with cocaine, AP-1 binding activity in the NAc remained elevated 18 h after the last chronic injection.
[130]	Protein phosphorylation and second messenger mechanisms possibly underly genetic vulnerability to alcoholism	Found that chronic opiates increase levels of the G-protein subunits Gi alpha and Go alpha, adenylate cyclase, cyclic AMP-dependent protein kinase, and some phosphoproteins (including tyrosine hydroxylase) in this brain region
[131]	Induction of chronic Fos-related antigens in rat brain by chronic morphine administration	Prolonged withdrawal periods induced Fos-related antigens (chronic Fras) in several brain regions, but not chronic morphine alone.
[132]	In the rat mesolimbic dopamine system axoplasmic transport is impaired by chronic morphine	Chronic morphine decreased axonal transport from the VTA to the NAc by 50%. However, consistent with its lack of effect on neurofilaments (NFs) in this brain region chronic morphine did not alter axonal transport from the locus coeruleus to several of its projection areas.
[133]	Behavioral, electrophysiological, and biochemical correlates of opiate withdrawal in the locus coeruleus (LC) of the rat	Increased LC neuronal activity is associated with temporally increased levels of G-proteins and an up-regulated cAMP system. These may contribute to the early-withdrawal activation of these neurons in behavioral morphine withdrawal syndrome
[134]	Morphine-reward and feeding are regulated by CREB, in the lateral hypothalamus.	The study revealed that opioids and stress induce increased transcription of CREB in the lateral hypothalamus which can effect both drug and food reward
[135]	Adenylyl cyclase-5 activity in the NAc regulates anxiety-related behavior	Administration of norbinaltorphimine (a kappa-opioid receptor antagonist) or CCK-8 s (a CCK receptor agonist) reversed the anxiolytic-like behavior exhibited by AC5−/− mutants. These results suggest an essential role of 5 adenylyl cyclase (AC5) in the NAc for maintaining healthy levels of anxiety.
[136]	LC behavioral adaptations to chronic emotional stimuli are controlled epigenetically by Histone deacetylase 5	Exposure to chronic but not acute cocaine or stress decreases HDAC5 function in the NAc in the brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes
[137]	The induction of Delta FosB in reward-related brain structures after chronic stress was studied.	Chronic restraint-stress induced DeltaFosB expression in several discrete regions of the brain, predominantly in the Frontal Cortex (fCTX), NAc, and basolateral amygdala, with lower levels of induction seen elsewhere. These findings establish that chronic stress induced DeltaFosB induction could contribute to the long-term effects of stress on the brain.
[138]	Hcrtr1 and 2 signaling differentially regulate depression-like behaviors.	Significantly reduced behavioral despair in the forced swim test and tail suspension test was displayed by Hcrtr1 null mice. Also, Wild-type mice treated with the hcrtr1 antagonist SB-334867 displayed a similar reduction in behavioral despair. These studies suggest the balance of orexin action at the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated.
[139]	Essential role for RGS9 in opiate action	A family of G protein signaling (RGS) regulators are known to accelerate effector stimulation termination after G protein receptor activation. A brain-specific splice variant of the RGS9 gene, RGS9-2, is highly enriched in the striatum and expressed at much lower levels in the periaqueductal gray and spinal cord structures known to mediate various actions of morphine and other opiates. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal.
[140]	Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.	Together, the results demonstrate that the nucleus accumbens CREB-dynorphin influence behavior in the learned helplessness model and suggest that this signaling cascade may contribute to symptoms of depression.
[141]	Epigenetic Basis of Mental Illness	Exposure to environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that epigenetic modifications maintain these sustained abnormalities in specific brain regions. Indeed, the transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders
[142]	The epigenetic mechanisms of chronic pain.	There is evidence that injury-induced changes in chromatin structure drive persistent cellular and molecular adaptations in gene expression and neural function, which may contribute to the development of several symptoms of chronic pain, including allodynia, hyperalgesia, anxiety, and depression.
[143]	Epigenetic mechanisms of drug addiction	Three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs are changes induced within the brain's reward regions by repeated exposure to drugs of abuse
[144]	Susceptibility to Social Defeat Stress is controlled by cell-type-specific epigenetic editing at the FosB gene	This demonstrates the first cell- and gene-specific targeted histone modifications, which model naturally occurring transcriptional phenomena that control social defeat stress behavior. This epigenetic-editing approach, which recapitulates physiological changes in gene expression, reveals clear differences in the social defeat phenotype induced by FosB gene manipulation in medium spiny neuron) MSN subtypes.
[145]	The mesolimbic dopamine reward circuit in depression	This study focused on the NAc ventral striatum, its dopaminergic input from the VTA and the potential role of the mesolimbic dopamine system in depression. The mesolimbic dopamine system is most often associated with the rewarding effects of food, sex, and drugs of abuse.
[146]	The role of DNA methylation within the nucleus accumbens in the incubation of cocaine craving	Withdrawal periods, and cue-induced cocaine seeking, were associated in this study with broad, time-dependent enhanced DNA methylation alterations in the NAc.
[147]	Inhibition of Class I, HDAC blocks cocaine-induced plasticity by targeted changes in histone methylation	This study demonstrates that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, induced repressive histone methylation and antagonized cocaine-induced changes in behavior. This effect was mediated in-part through a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons.
[148]	The expression of the RhoA network in the NAc to control synaptic structure is augmented by withdrawal from chronic morphine administration	The nucleus NAc is a critical reward region of the brain that mediates the effects of psychoactive substances including morphine and other opiates. An important role for hippocampal RhoA in morphine-facilitated reward behavior. Recent work revealed an important role for RhoA signaling cascades in mediating the effects of long-term morphine withdrawal on NAc MSN dendritic spine elimination.
[149]	Histone arginine methylation was observed in cocaine action in the NAc	Src kinase (Srcin1), signaling inhibitor also referred to as (p140Cap) is a key gene target for reduced H3R2me2a binding. These findings suggest that PRMT6 and H3R2me2a down-regulation suppression of Src signaling in NAc D2-MSNs, via, functions is a homeostatic brake to restrain cocaine action. This finding may provide novel candidates for the development of treatments for cocaine addiction-like Pro-dopamine regulator (KB220).
[150]	Histone acetylation in drug addiction	Regulation of chromatin structure through post-translational modifications of histones (e.g., acetylation) has emerged as an important mechanism to translate a variety of environmental stimuli, including drugs of abuse, into specific changes in gene expression.
[151]	The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons	The striatum plays a crucial role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). We now know there are two MSN subtypes (direct & indirect) in the long-term actions of drugs of abuse.
[152]	The epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area was delineated	Found that morphine suppressed binding of phospho-CREB (cAMP response element-binding protein) to Bdnf promoters in VTA, which resulted from the enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine.
[153]	Proenkephalin (Penk) mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability	Following adolescent Δ(9)-tetrahydrocannabinol (THC) exposure, enhanced heroin self-administration (SA) and dysregulation of the endogenous opioid system in the NAc shell (sh) of adults has been demonstrated in animal studies. A direct association between heroin self-administration and THC-induced NAcsh Penk upregulation indicate that epigenetic dysregulation of Penk underlies the long-term effects of THC were established by this data.