Research Highlights:Highlights from the latest articles in epigenomics & addiction

Epigenetic Modifications: Significance in Drug Addiction and Treatment

Evaluation of: Sanchis-Segura C, Lopez-Atalaya JP, Barco A: Selective boosting of transcriptional and behavioral responses to drugs of abuse by histone deacetylase inhibition. Neuropsychopharmacology 34(13), 2642–2654 (2009); Malvaez M, Sanchis-Segura C, Vo D et al.: Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol. Psychiatry 67(1), 36–43 (2010).

Chronic use of addictive drugs, such as cocaine and heroin, often leads to drug tolerance and physical and psychological dependence. The complex behavioral changes induced by drugs of abuse, which ultimately lead to addiction, are believed to result from molecular and cellular adaptations in specific regions of brain, including the nucleus accumbens and the ventral tegmental area. One mechanism implicated in the drug-induced adaptation or plasticity process involves long-term alterations in gene-expression patterns and changed regulation of gene expression in addiction-related brain regions induced by repeated exposures to drugs. Increasing evidence suggests that the epigenetic mechanisms that remodel chromatin structure at the gene promoter regions contribute to the persistent changes in gene expression and behavior. After repeated drug administration, transcription factors, such as ΔFosB, were found to accumulate in the striatum, a major brain locus affected by addictive drugs, and this appears to induce increased cocaine locomotor sensitization and reward [1]. The groundbreaking study by Kumar and colleagues revealed that repeated cocaine exposure induces a persistent increase in histone H3 acetylation at the promoters of BDNF and CDK5 (a gene regulated by ΔFosB) in the striatum, and the inhibition of histone deacetylase increases the locomotor and conditioned place preference responses to cocaine [2]. Levine et al. further demonstrated that the CREB-binding protein controls the response to cocaine by acetylating histones at the fosB promoter in the striatum [3].

Accumulating evidence has demonstrated that regulation of the histone acetylation level by histone acetyltransferases and deacetylases (HDAC) plays a key role in the development of drug addiction. However, to date, most research in the area has primarily concentrated on a particular class of abuse drug, such as cocaine. Sanchis-Segura and colleagues recently reported their investigation into the effects of inhibition of HDACs on behavioral responses induced by three drugs of different classes: psychostimulant, alcohol and opioid [4]. They first evaluated the effect of the application of HDAC inhibitor sodium butyrate on locomotor sensitization induced by cocaine, ethanol and morphine, and observed that mice treated with sodium butyrate developed an enhanced locomotor response (sensitization) to all three drugs. Moreover, the effects of HDAC inhibition are highly persistent. Significantly increased locomotor sensitization response induced by a single dose of cocaine, ethanol or morphine could be observed 1 week later in mice that previously received the corresponding drugs and the pretreatment of sodium butyrate, compared with those that received saline pretreatment. In addition to the effect on sensitization of locomotor behavior, repeated administration of drugs also induces behavioral alterations, such as tolerance and physical dependence. Intriguingly, Sanchis-Segura and colleagues found that the application of HDAC inhibitor sodium butyrate selectively enhances some but not all of the behavioral responses to chronic administration of these three drugs. For instance, they demonstrated elegantly that HDAC inhibitor pretreatment augments morphine-induced increased sensitization of locomotor activity and conditioned place preference; however, they failed to demonstrate a significant effect on the development of tolerance to morphine analgesia and naloxone-precipitated withdrawal symptoms [4]. Similarly, pretreatment with sodium butyrate showed no effect on ethanol tolerance or withdrawal [4]. Their data implicate that the upregulation of gene expression by histone acetylation induced by chronic administration of drugs may be particularly important for the development of psychological but not physical dependence. Consistent with their proposal, Wang et al. reported very recently that chronic cocaine-induced histone H3 acetylation and transcriptional activation of CaMKII α in the nucleus accumbens is critical for motivation for drug reinforcement [5]. Using a microarray approach, Sanchis-Segura et al. further demonstrated that HDAC inhibitor pretreatment selectively enhances the expression of genes that are activated by chronic morphine and highly relevant to neuroplasticity and addiction, including circadian clock genes. It is known that the transcription of clock genes, such as PER1, is regulated by drug-induced hyperacetylation of histone at the corresponding gene promoters. The work of Sanchis-Segura et al. thus supports a critical role of chronic drug administration-induced histone acetylation at the promoters of addiction-related genes in the development of long-lasting adaptive changes in plasticity of the neurocircuitry of reward- and addiction-related behavioral properties.

Recent work by Malvaez et al. provided the first piece of evidence on the effect of chromatin remodeling on the extinction of drug-induced behavioral changes, implicating the potential therapeutic value of HDAC inhibitors and pharmacological manipulation of histone acetylation in the treatment of substance abuse [6]. Using a conditioned place preference mouse model, they elegantly demonstrated that mice that received systemic administration of sodium butyrate immediately after extinction training extinguished cocaine addiction-related behaviors more rapidly and to greater extent than those that received saline injection, and these HDAC inhibitor-treated animals spent significantly less time in the previously cocaine-paired compartment after challenge with a prime injection of cocaine, indicating an attenuated reinstatement of drug seeking. Furthermore, paralleled with the enhanced extinction and attenuated reinstatement of conditioned place preference, administration of the HDAC inhibitor significantly increased H3 acetylation in the nucleus accumbens, a brain region highly relevant to drug addiction, after extinction of cocaine-conditioned place preference, implicating an important role of histone acetylation [6]. The physiological and pharmacological significance of drug-induced chromatin remodeling and transcriptional activation in the development of drug addiction has been increasingly recognized, although the underlying mechanisms by which chronic use of addictive drugs induces epigenetic modification of histones at promoters of specific genes are yet to be fully understood. Accumulating evidence shows that epigenetic regulation of gene expression induces changes in addictive behaviors, such as motivation and sensitization. The findings of Malvaez and co-workers provide a potential novel pharmacological approach to the development of improved treatments that counteract neural adaptation leading to addiction and facilitate extinction of drug-seeking behavior.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Antidepressant Actions of Histone Deacetylase Inhibitors

Evaluation of: Covington HE, Maze I, LaPlant QC et al.: Antidepressant actions of histone deacetylase inhibitors. J. Neurosci. 29 (37), 11451–11460 (2009)

Depression, like drug addiction, is a chronic psychiatric disorder. The neurobiology of depression and the molecular pharmacology of antidepressant action are both poorly understood. Medicine used currently for antidepressant treatment exerts immediate impact on the monoamine system, but, interestingly, its antidepressant effects require several weeks of treatment. This suggests the potential involvement of stable adaptation of gene-expression patterns in the brain, which may be regulated by chromatin remodeling, such as histone modification [1].

Histone acetylation, which generally results in the upregulation of gene expression, is regulated by histone acetyltransferase and histone deacetylase (HDAC). The application of a HDAC inhibitor attenuates deaceylation of histones and, thus, elevates levels of histone acetylation. Chronic administration of imipramine, a tricyclic antidepressant, induces long-lasting histone hyperacetylation at promoters of brain-derived neurotrophic factor, and overexpression of HDAC in the hippocampus blocks the inhibitory effect of imipramine on depression-like behavior in mice that have experienced social defeat stress [2]. Further studies demonstrated that systemic administration of sodium butyrate, a nonspecific HDAC inhibitor, induces a transient hyperacetylation of histones in certain brain regions, including the frontal cortex and the hippocampus, and that sodium butyrate exerts an antidepressant-like effect [2,3]. These studies implicate that the modulation of gene expression by histone acetylation may be one of the mechanisms of antidepressant action. However, a causal relationship between changed acetylation and gene expression mediated by sodium butyrate and its antidepressant-like effect, and the brain regions and target genes that mediate the antidepressant-like effects of HDAC inhibition remains to be demonstrated. Covington and colleagues recently demonstrated that chronic social defeat stress in mice and clinical depression are associated with increased levels of H3 acetylation at lysine 14 in the nucleus accumbens, an important limbic brain region for expression of reward- and stress-related behaviors [4]. The experience of chronic social defeat stress experience induces a transient decrease, followed by a persistent increase, in the levels of acetylated histone H3 in the nucleus accumbens, accompanied by decreased levels of HDAC2 in the same brain region. Moreover, similar effects were also observed in human depression. They further demonstrated that, when infused into the nucleus accumbens, HDAC inhibitors, suberoylanilide hydroxamic acid and MS-275 not only significantly increase levels of H3 acetylation at lysine 14 but also exert robust antidepressant-like effects in the social defeat paradigm and other behavioral assays [4]. Data from gene-expression arrays further revealed that the unique pattern of gene expression in the nucleus accumbens induced by chronic social defeat induced-stress can be reversed by either the HDAC inhibitor MS-275 or the classic antidepressant fluoxetine. The findings of Covington et al. underscore an important role for histone remodeling in the pathophysiology and pharmacology of antidepressants and provide support for the therapeutic potential for HDAC inhibitors in depression treatment.

Smoking Induces Persistent Epigenetic Regulation

Evaluation of: Launay J-M, Del Pino M, Chironi G et al.: Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation. PLoS ONE 4(11), E7959 (2009)

Smoking is a major public health problem affecting multiple systems, and approximately 3 million people die from smoking-related disorders each year. The mechanisms underlying smoking behavior and toxicity are still largely unknown. Studies have demonstrated a strong association between smoking and depression. One of the molecular targets to link smoking with depression is monoamine oxidase (MAO), an enzyme that plays a key role in the metabolism of endogenous amines, such as serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine, and xenobiotics. MAO inhibitors possess antidepressant activities and are used to treat depression and tobacco addiction or tobacco weaning [1,2]. Inhibitors of 5-HT uptake are also used in the treatment of depression and other psychiatric disorders [3]. In a recently published study, Launay and co-workers reported that, unexpectedly, the significant change in 5-HT catabolism was found in former smokers, rather than nonsmokers (who had stopped smoking for an average of 13 years) or current smokers [4]. Compared with nonsmokers or current smokers, the former-smoker group displayed significantly reduced platelet 5-HT, increased platelet MAO activity and plasma 5-HT/MAO catabolites. Their data indicate that the MAO-B activity is inhibited by smoking, whereas the platelet MAO protein level is increased during smoking, possibly a result of the compensational response to the inhibition of MAO activity. Furthermore, such an increase in MAO-B protein could be observed in former smokers who had quit smoking for an average of 13 years [4]. The long-lasting change in MAO level suggests that smoking may induce activation of MAO gene expression. Therefore, Launay et al. analyzed the methylation patterns of the MAOB core promoter in a small supplementary cohort of similar subjects. Their results indicate that smoking increases nucleic acid demethylase activity, reduces methylation of the MAOB promoter and results in an increase of MAO expression [4].

In summary, the interesting findings of Launay et al. represent the first report of the regulation of chromatin modification by smoking. The reduced methylation of smoking-related gene promoters as well as the regulation of expression of target genes provides a new pathological mechanism for smoking. Although the results warrant further studies in a larger sample size with more analyses, this study highlights the potential significance of smoking-induced epigenetic modification and its long-lasting effects after quitting smoking.