Addiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review ...the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual’s vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction. We conclude by exploring how epigenetic mechanisms might serve as therapeutic targets for addiction treatments.
Here, Nestler and Lüscher link addiction circuits to epigenetic mechanisms that are engaged by drug exposure or reflect life experience. These molecular alterations may not only explain the basis of drug-evoked synaptic plasticity, but may also help understand individual addiction vulnerability.
Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and ...functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes ...suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation—histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes.
This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.
•Epigenetic regulation mediates adaptations to the environment such as abused drugs.•Epigenetic regulation includes post-translational modifications of histones.•Epigenetic regulation also includes DNA methylation and non-coding RNAs.•Each of these epigenetic mechanisms are influenced by drugs of abuse.•In turn, these epigenetic mechanisms control behavioral responses to the drugs.
Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the ...addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors ΔFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-κB (NF-κB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Growing evidence supports the hypothesis
that epigenetics is a key mechanism through which environmental exposures interact with an individual’s genetic constitution to determine risk for depression ...throughout life.
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Epigenetics, in its broadest meaning, refers to stable changes in gene expression that are mediated via altered chromatin structure without modification of DNA sequence. According to this hypothesis, severe stress triggers changes—in vulnerable individuals—in chromatin structure at particular genomic loci in the brain’s limbic regions, which drive sustained changes in gene expression that contribute to episodes of depression. A corollary of this hypothesis is that such stress-induced epigenetic modifications also occur early in life and help determine an individual’s lifetime vulnerability or resistance to subsequent stressful events.
Regulation of gene expression is considered a plausible mechanism of drug addiction, given the stability of behavioural abnormalities that define an addicted state. Among many transcription factors ...known to influence the addiction process, one of the best characterized is ΔFosB, which is induced in the brain's reward regions by chronic exposure to virtually all drugs of abuse and mediates sensitized responses to drug exposure. Since ΔFosB is a highly stable protein, it represents a mechanism by which drugs produce lasting changes in gene expression long after the cessation of drug use. Studies are underway to explore the detailed molecular mechanisms by which ΔFosB regulates target genes and produces its behavioural effects. We are approaching this question using DNA expression arrays coupled with the analysis of chromatin remodelling-changes in the posttranslational modifications of histones at drug-regulated gene promoters-to identify genes that are regulated by drugs of abuse via the induction of ΔFosB and to gain insight into the detailed molecular mechanisms involved. Our findings establish chromatin remodelling as an important regulatory mechanism underlying drug-induced behavioural plasticity, and promise to reveal fundamentally new insight into how ΔFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.
Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental ...events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities.
Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are ...impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There has been increasing interest in the possibility that behavioral experience--in particular, exposure to stress--can be passed on to subsequent generations through heritable epigenetic ...modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility--and the experimental evidence for and against the existence of such mechanisms--and outlines steps required for future investigations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Major depressive disorder is a heritable psychiatric syndrome that appears to be associated with subtle cellular and molecular alterations in a complex neural network. The affected brain regions ...display dynamic neuroplastic adaptations to endocrine and immunologic stimuli arising from within and outside the CNS. Depression's clinical and etiological heterogeneity adds a third level of complexity, implicating different pathophysiological mechanisms in different patients with the same DSM diagnosis. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are themselves incompletely understood. This review summarizes the current knowledge of the neurobiology of depression by combining insights from human clinical studies and molecular explanations from animal models. The authors provide recommendations for future research, with a focus on translating today's discoveries into improved diagnostic tests and treatments.
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