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, 128, 51-87

Histone-mediated Epigenetics in Addiction


Histone-mediated Epigenetics in Addiction

Leah N Hitchcock et al. Prog Mol Biol Transl Sci.


Many of the brain regions, neurotransmitter systems, and behavioral changes that occur after occasional drug use in healthy subjects and after chronic drug abuse in addicted patients are well characterized. An emerging literature suggests that epigenetic processes, those processes that regulate the accessibility of DNA to regulatory proteins within the nucleus, are keys to how addiction develops and how it may be treated. Investigations of the regulation of chromatin, the organizational system of DNA, by histone modification are leading to a new understanding of the cellular and behavioral alterations that occur after drug use. We will describe how, when, and where histone tails are modified and how some of the most recognized histone regulation patterns are involved in the cycle of addiction, including initial and chronic drug intake, withdrawal, abstinence, and relapse. Finally, we consider how an approach that targets histone modifications may promote successful treatment.

Keywords: Addiction; Epigenetics; Histone; Learning; Memory.


Figure 1
Figure 1. Epigenetic changes in the cycle of addiction
Some of the potential chromatin dynamics are shown for the cycle of addiction, which moves from acute exposure, to chronic drug taking, to withdrawal, to abstinence and recovery, and finally back to acute exposure in cases of relapse, which begins the cycle again. Three potential states of chromatin (i.e., OPEN, CLOSED, or INTERMEDIATE) and their associated nuclear changes are depicted within four small gray boxes (numbered 1–4). These chromatin states create a more accessible (Box 2), inaccessible (Box 3), or intermediate (Box 1 and 3) structure for DNA to be accessed and transcription to take place. The top half of this figure signifies chromatin in a more “adaptive and responsive” state. The bottom half signifies chromatin in a more “inflexible and unresponsive” state (splitting states 2 and 4 into both of these categories evenly). The left half of this figure signifies a more “heterochromatin” state, while the right half signifies a more “euchromatin” state (splitting states 1 and 3 into both of these categories). Dashed lines (e.g. +chronic, +relapse, +treatment) represent the potential for associated changes to be accelerated by rate and/or intensity. Box 1 (INTERMEDIATE chromatin before drug intake) represents a basal chromatin state with normal transcription (determined primarily by genetic and previous environmental interactions). In this state, the chromatin and associated nuclear changes are well balanced and highly regulated. Box 1→Box 2 Transition: With acute exposure to stress or drugs of abuse, brief and reversible changes (see bi-directional arrows) occur to select histone and DNA regions (increased histone acetylatransferases like CREB-binding protein [CBP], acetylation, DNA accessibility, learning and memory related gene transcription). Box 2 (OPEN chromatin) represents the change that occurs with a single or acute insult to the system (e.g., acute stress or drug exposure). Chromatin expands, releasing repressive marks and tipping the balance of epigenetic regulation towards those associated with gene activation. Box 2→Box 3 Transition: With repeated exposure to stress or drugs, a prolonged and less reversible change occurs to select histone and DNA regions. Box 3 (INTERMEDIATE chromatin after drug intake) represents chromatin with dysregulated histone enzymes, marks, transcription factors (TFs) and transcription. In this state, similar process occur as in Box 1, yet the location where histone modifications occur, the type of modification, and the effect that histone modifications have on cellular and behavioral outcomes is altered to positively reinforce this chromatin state. The balance of regulation is shunted away from promoter regions that are associated with learning and adaption (cFos, BDNF) and shifted toward promoter regions that are associated with this altered chromatin state and positively reinforce this altered gene regulation (e.g., Ras and ΔFosB). These changes are thought to induce increased cellular tolerance and maladaptive behavior. Box 3→Box 4 Transition: With acute drug abstinence, brief and reversible changes occur to select histone and DNA regions (increased histone deacetylases, methylation, DNA inaccessibility, decreased gene transcription) in an attempt to rebalance the previous dysregulation. Yet, after chronic or repeated insults to the system recent drug abstinence induces withdrawal associated effects (e.g., anxiety and depression) making the organism increasingly susceptible to relapse rather than recovery and long-term treatment. Box 4 (CLOSED chromatin) represents the change that occurs with acute abstinence (without relapse) and the associated withdrawal from drugs of abuse. Here chromatin begins the process of rebalancing enzyme levels, histone marks, and gene transcription by generally increasing the repression of prior imbalances related to addiction. The previous epigenetic and behavioral changes placed on the system (e.g., positive feedback of ΔFosB and behavioral depression) make this process slow, the system resistant to rebalancing, and deprived of necessary proteins to counteract this state. As chromatin becomes more condensed, regulation is increased (although exceptions to this mechanism exist, such as decreases to repressive methylation with withdrawal, noted in Section 5.3). Transition from Box 4→Box 1: With repeated and long-term abstinence from drug use a prolonged and less reversible change occurs to select chromatin regions, rebalancing the location, type, and effect that histone modifications have on cellular and behavioral outcomes, recovering to a more normal and highly regulated level of transcription.

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