Trends in Molecular Medicine
ReviewEpigenetic mechanisms in drug addiction
Section snippets
Mechanisms of drug addiction
Drug addiction is a debilitating psychiatric disorder that is characterized by compulsive drug seeking and taking despite severe adverse consequences 1, 2, 3. Once an individual becomes addicted to a drug of abuse, there are few effective clinical options, and most addicts relapse within a short period of time. Thus, addiction research focuses on two major outstanding questions. First, what are the neural mechanisms underlying the transition from recreational drug use to a chronically addicted
Epigenetic mechanisms
The word ‘epigenetic’ historically refers to a heritable phenotype not coded by DNA itself but by a cellular process ‘above the genome’. Cellular differentiation is a classic example where epigenetic phenomena have a critical role 20, 21. Because all cells in an organism contain the same genetic information, the ability to form clonal populations of distinct cell types with unique functions (e.g. neurons versus hepatocytes) is achieved by transmitting the correct transcriptional programs from
Histone acetylation
Acetylation of histone lysine residues reduces the electrostatic interaction between histone proteins and DNA, which is thought to relax chromatin structure and make DNA more accessible to transcriptional regulators [28]. Histone acetylation is best characterized on histones H3 and H4: it can occur on lysines 9, 14, 18 and 23 on the N-terminal tail of H3 and at lysines 5, 8, 12 and 16 on the tail of H4. Genome-wide studies have shown that hyperacetylation in promoter regions is strongly
Role of epigenetic mechanisms in drug-related behaviors
The identification of cocaine-induced alterations in histone acetylation, phosphorylation and methylation in the NAc and other brain areas suggests that such modifications might be involved in regulating behavioral responses to drugs of abuse. Indeed, the first evidence for this came from studies that demonstrated that the pharmacological and genetic manipulation of certain HDACs in the NAc alters levels of histone acetylation in vivo and profoundly affects behavioral sensitivity to cocaine [17]
Interplay between transcription factors and epigenetic mechanisms
In order for environmental stimuli to regulate chromatin structure on the correct set of genes, mechanisms exist to guide the proper chromatin-remodeling enzymes and transcriptional regulators to the right gene locus. Transcription factors serve as a key mechanism by which distinct gene programs are controlled because they bind to highly specific DNA regulatory sequences. These regulatory sequences – termed response elements – serve as an address, so the cell can rapidly initiate specific gene
Future studies
Drug-induced alterations in chromatin structure have now been implicated in both the pathogenesis and maintenance of the addicted state. An important area for future research is to translate these findings from simple behavioral models, such as conditioned place preference and locomotor responses, to self-administration and relapse paradigms, which better model the human syndrome. Moreover, cocaine and other related stimulant addiction makes up only a small part of the substance abuse problem,
Concluding remarks
There is now growing evidence that epigenetic mechanisms, such as histone acetylation, are involved in the regulation of the saliency of environmental stimuli in several behavioral models 17, 18, 19, 24, 33, 34, 42, 51, 62. This has important implications for the pathogenesis of drug addiction and other neuropsychiatric disorders because novel therapeutics could target such mechanisms to block or even reverse the transition from recreational drug use to a chronically addicted state. Likewise,
Acknowledgements
Preparation of this review was supported by grants from the National Insitute on Drug Abuse (E.J.N.) and the University of Texas Southwestern Medical Scientist Training Program (W.R.).
References (72)
Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission
Neuron
(2005)Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments
Neuron
(1994)ΔFosB: a molecular switch for long-term adaptation in the brain
Brain Res. Mol. Brain Res.
(2004)Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking
Neuron
(2004)Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity
Neuron
(2004)Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum
Neuron
(2005)Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli
Neuron
(2007)Genome regulation by polycomb and trithorax proteins
Cell
(2007)- et al.
The histone tails of the nucleosome
Curr. Opin. Genet. Dev.
(1998) The role of chromatin during transcription
Cell
(2007)
Chromatin modifications and their function
Cell
Mapping global histone acetylation patterns to gene expression
Cell
Genome-wide map of nucleosome acetylation and methylation in yeast
Cell
Regulation of histone acetylation during memory formation in the hippocampus
J. Biol. Chem.
Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin
Mol. Cell
Heritable gene repression through the action of a directed DNA methyltransferase at a chromosomal locus
J. Biol. Chem.
Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice
Behav. Brain Res.
Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR
Mol. Cell
Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse
Biol. Psychiatry
Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications
Chem. Biol.
Maternal care as a model for experience-dependent chromatin plasticity?
Trends Neurosci.
Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy
Cell
Circadian regulator CLOCK is a histone acetyltransferase
Cell
Covalent modification of DNA regulates memory formation
Neuron
Neural mechanisms of addiction: the role of reward-related learning and memory
Annu. Rev. Neurosci.
Stress, dysregulation of drug reward pathways, and the transition to drug dependence
Am. J. Psychiatry
Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine
Nature
Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving
J. Neurosci.
Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse
Nat. Neurosci.
A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal
J. Neurosci.
Chronic cocaine-mediated changes in non-human primate nucleus accumbens gene expression
J. Neurochem.
Regulation of gene expression and cocaine reward by CREB and ΔFosB
Nat. Neurosci.
Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area
J. Neurosci.
ΔFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction
J. Neurosci.
Differential gene expression in the rat caudate putamen after ‘binge’ cocaine administration: advantage of triplicate microarray analysis
Synapse
CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum
Proc. Natl. Acad. Sci. U. S. A.
Cited by (327)
Epigenomic profiling of mouse nucleus accumbens at single-cell resolution
2023, Molecular and Cellular NeuroscienceFuture perspectives of emerging novel drug targets and immunotherapies to control drug addiction
2023, International ImmunopharmacologyTranscriptional and epigenetic regulation of microglia in substance use disorders
2023, Molecular and Cellular NeuroscienceCharacterization of grass carp FosB, Fosl2, JunD transcription factors in response to GCRV infection
2022, Aquaculture and Fisheries