ReviewHistone acetylation in drug addiction
Introduction
Drug addiction is a chronic psychiatric condition of compulsive drug seeking and taking despite severe social and physical repercussions [1], [2], [3], [4]. One of the most clinically challenging aspects of addiction is its persistence even after long periods of drug abstinence, which is highlighted by high rates of drug relapse for most addictive drugs. All drugs of abuse in some way converge on the mesolimbic dopamine system, a key brain circuit involved in reward [1], [3]. This circuit normally helps determine how rewarding certain environmental stimuli are and functions to reinforce evolutionally favorable activities, such as eating fatty foods or sex [5]. The dopaminergic cells of the ventral tegmental area (VTA) project into the forebrain and bathe several key limbic structures with dopamine, including the nucleus accumbens (NAc). The NAc integrates inputs from the prefrontal cortex (PFC), amygdala, hippocampus, and several other limbic structures to synthesize the appropriate synaptic and behavioral responses to rewarding stimuli including drugs of abuse [1], [3]. Addictive drugs such as cocaine have been shown to induce long-lasting structural, electrophysiological, and transcriptional changes in the NAc, and some of these changes have been linked to addictive behaviors such as drug self-administration and relapse [1], [2], [3], [4]. One of the best studied examples is the transcription factor ΔFosB, a splice product of the immediate early gene fosB, which accumulates several fold in the NAc after repeated drug exposure due to its protein stability [6], [7], [8]. The drug-induced accumulation of ΔFosB contributes to addiction-related behaviors, as its overexpression in the NAc sensitizes mice to the locomotor-activating and rewarding effects of cocaine and morphine [9], [10], as well as promotes the motivation to self-administer cocaine [11]. In addition to ΔFosB, gene expression microarrays have been used to identify other dysregulated genes in the NAc that may also contribute to the addicted state [12], [13], [14], [15], [16], [17], [18]. These genome-wide studies begin to illustrate the potent regulatory control drugs of abuse have on gene activity in the NAc, as numerous genes are up- or down-regulated in response to chronic drug exposure. While much is known about the upstream signaling mechanisms initiated by drug-induced increases in dopamine and other neurotransmitters in the NAc [1], [2], [3], [4], far less is known about the downstream mechanisms which integrate neurotransmitter signaling into long-lasting genome-wide alterations in transcription.
A key cellular mechanism that integrates diverse environmental stimuli with changes in gene expression is chromatin remodeling [19], [20]. Signal-dependent enzymes can alter the structure of chromatin at specific gene loci to facilitate the activation or repression of specific transcriptional programs. Chromatin is made up of DNA and the histone proteins around which the DNA is wrapped. Histones are assembled into an octamer composed of two copies each of H2A, H2B, H3, and H4 [21]. Through a complex process not completely understood, chromatin is supercoiled into a highly condensed structure that packages and organizes many meters of DNA into the nucleus of each cell. This highly condensed structure provides chromatin unique control over gene expression by gating access of transcriptional activators to DNA [22], [23]. Chromatin structure itself is regulated at specific gene loci by numerous mechanisms that serve to either physically relax (e.g., histone acetylation) or remodel (e.g., SWI-SNF-dependent nucleosome remodeling) chromatin structure, or provide docking sites to recruit additional transcriptional co-activators or repressors [24]. Such modifications include histone acetylation, phosphorylation, and methylation, among several others, which together determine the activity of the underlying gene [19], [24]. This review discusses the recent evidence that changes in histone acetylation, and the enzymes which control it, contribute to drug-induced alterations in gene expression and behavior. While histone acetylation is the best studied modification in brain, it should be emphasized that other chromatin modifications typically occur in parallel and also likely participate in the long-term plasticity underlying drug addiction.
Section snippets
Histone acetylation
Histone acetylation occurs on histones H2A, H2B, H3, and H4, but it is best described in brain on H3 where it can occur on the N-terminal tails at lysines 9, 14, 18, and 23 and on H4 at lysines 5, 8, 12, and 16 [24]. Histone acetylation is thought to affect the activity of a gene through two main mechanisms. First, acetylation of lysine residues reduces their positive charge and thus their electrostatic attraction to the negatively charged backbone of DNA. This reduced electrostatic attraction
Cocaine/amphetamine
Cocaine and amphetamine substantially elevate dopamine levels in several forebrain regions involved in reward processing such as the NAc and PFC [1], [51]. The molecular changes induced by cocaine and amphetamine in brain reward regions are typically studied in rodents using investigator-administered or self-administered drug paradigms. Investigator-administration is a relatively high throughput method used to examine differences caused by acute or chronic drug exposure at varying time points
Histone acetyltransferases
As discussed above, HATs are enzymes which catalyze the addition of acetyl groups onto histone proteins. One of the best studied HATs is CBP, which is known to associate with phosphorylated CREB and assist in target gene activation [36], [69]. While cocaine increases H4 acetylation on the fosb promoter in striatum of wild type mice, this does not occur in CBP-deficient mice [34]. Moreover, this cocaine-induced acetylation event on fosb and perhaps other genes may be behaviorally important, as
Functions of histone acetylation in vivo
These studies in drug abuse, together with findings in models of leaning and memory, depression, and chronic pain, suggest that histone acetylation controls the saliency of a wide variety of environmental stimuli [20], [34], [53], [54], [57], [58], [79], [80]. In fear conditioning, a commonly used behavioral test of learning and memory, HDAC inhibitors significantly improve formation of long-term memory [57], [58]. In social defeat stress, a behavioral model which elicits a depression-like
Future studies and challenges
While drug-induced alterations in histone acetylation have to date been implicated in the behavioral responses to drugs of abuse in simple models such as conditioned place preference and locomotor assays, future research is needed to translate these findings to more sophisticated models of human addiction, such as self-administration and relapse paradigms. These pre-clinical behavioral models can directly assess the role of histone acetylation in the pathogenesis and maintenance of the addicted
Conclusions
Histone acetylation has been shown to be involved in modulating the saliency of many environmental stimuli. Conditions which increase levels of histone acetylation appear to sensitize mice to cocaine, stress and pain, while conditions that reduce histone acetylation diminish sensitivity to these stimuli. This has important implications in the pathogenesis of drug addiction, depression, chronic pain, and memory disorders. Ultimately, the key function of histone acetylation is to increase the
Acknowledgements
Preparation of this review was supported by grants from NIDA (EJN) and the UT Southwestern Medical Scientist Training Program (WR).
References (88)
- et al.
Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission
Neuron
(2005) - et al.
Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity
Neuron
(2004) - et al.
The histone tails of the nucleosome
Curr Opin Genet Dev
(1998) - et al.
The role of chromatin during transcription
Cell
(2007) Chromatin modifications and their function
Cell
(2007)- et al.
Mapping global histone acetylation patterns to gene expression
Cell
(2004) - et al.
Genome-wide map of nucleosome acetylation and methylation in yeast
Cell
(2005) - et al.
Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14
Mol Cell
(2000) - et al.
Chromatin acetylation, memory, and LTP are impaired in CBP± mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration
Neuron
(2004) - et al.
CBP histone acetyltransferase activity is a critical component of memory consolidation
Neuron
(2004)