Epigenetics of Cocaine Addiction: Your Brain on Drugs
The dramatic behavioral changes induced by cocaine, such as hyperactivity, are accompanied by post-translational modifications (PTMs) of histones. These modifications result in altered gene expression in the area of the brain known as the nucleus accumbens (NAc), which is associated with pleasure. Past research pointed to the use of histone deacetylase (HDAC) inhibitors as a potential therapy for cocaine addiction. However, there is limited knowledge about both the roles different HDACs have following cocaine use, and how HDAC inhibitors could act to counter those effects. Now, a recent study by Kennedy et al. reveals a mechanism underlying HDAC1 inhibitor-mediated blockade of cocaine-induced molecular and behavioral plasticity via PTMs of histones.
The authors first determined that HDAC1 was responsible for modulating the behavioral effects of cocaine in mice because only a knockdown of HDAC1, not HDACs 2 or 3, resulted in significant reduced locomotor sensitization to cocaine. A selective HDAC1 inhibitor, MS-275, was then tested by infusing it into the brain of mice; this resulted in reduced hyperactivity similar to what was observed during the knockdown. Furthermore, chronic MS-275 infusion resulted in increased global acetylation of histone H3 at Lys9 (H3K9ac) and Lys14 (H3K14ac) in both the presence and absence of cocaine. MS-275 treatment also resulted in some cocaine-specific changes in histone modification patterns. Levels of the repressive modifications H3K9me2 and H3K9me3 increased with MS-275 treatment, but only following cocaine use. However, long-term, not acute, infusion of MS-275 was required for significant attenuation of locomotor activity and increased H3K9me2 levels. Other histone modifications that did not change with repeated cocaine use, such as H3K4me3 or H3K27me3, were also not changed by MS-275 treatment.
To understand the mechanism responsible for the elevated H3K9me2 and H3K9me3 levels following cocaine use during MS-275 treatment, the authors screened the expression of three lysine methyltransferases (KMTs) known for catalyzing these modifications: Ehmt2, Ehmt1, and Suv39hI. Only Ehmt2 expression was downregulated after cocaine administration, but with MS-275 treatment, Ehmt2 and Suv39hI expression increased. Furthermore, quantitative chromatin immunoprecipitation (qCHIP) showed increased H3K9ac association at promoters of all three KMTs. These results show MS-275 treatment elevated acetylation levels at KMTs promoters, allowing increased expression of KMTs that can catalyze repressive histone methylation. Without HDAC1 inhibition, HDAC1 binding to the promoters of Ehmt2 and Ehmt1 increased after repeated cocaine administration. This suggests that HDAC1 mediates cocaine-induced PTMs by deacetylating the promoter regions of KMTs to suppress enzyme expression, resulting in decreased repressive histone methylation and increased expression of other downstream genes.
Since cocaine-induced behavioral plasticity requires reduced levels of H3K9me2 in NAc, the authors hypothesized that increased repressive H3K9me2 after MS-275 treatment may be key to blocking the behavioral changes. Therefore, they screened possible gene targets known to be upregulated and associated with the behavioral changes in response to cocaine. GABAA receptor subunits, which mediate inhibitory postsynaptic currents (IPSCs) in spiny neurons, were of interest because previous studies demonstrated that cocaine-induced behavior changes correlated with increased expression of GABAA receptor. Infusion of bicuculline, a GABAA inhibitor, blocked locomotor sensitization to cocaine, confirming the role of GABAA receptor in mediating cocaine-induced behaviors. MS-275 treatment with cocaine reduced GABAA receptor subunit gene expression concomitant with a dramatic increase in repressive H3K9me2 marks at the GABAA subunit gene promoter. These results suggested that MS-275 reduces cocaine-induced behavioral plasticity via inducing repressive lysine methylation of the GABAA receptor gene promoter region, leading to reduced IPSCs.
In summary, the authors propose that MS-275 inhibits HDAC1 activity, which increases H3 acetylation levels at the promoters of KMTs, promoting their expression. Increased levels of KMTs catalyze repressive histone methylation of the GABAA receptor subunit gene promoter to reduce GABAA subunit expression. This interferes with IPSCs in spiny neurons and, therefore, blocks the behavioral effects of cocaine. This study reveals the mechanism that the HDAC1 inhibitor MS-275 utilizes to block cocaine-induced plasticity and gives further insight into the complex interplay between different PTMs of histones in regulating brain function. Furthermore, this report suggests that epigenetic drugs could potentially be used as treatments for neurological disorders and addiction therapy.
Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, & Nestler EJ (2013). Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nature neuroscience, 16 (4), 434-40 PMID: 23475113
Link to abstract: http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3354.html