Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015;10(7):574-80.
doi: 10.1080/15592294.2015.1055441.

Epigenetic landscape of amphetamine and methamphetamine addiction in rodents

Arthur Godino  1 , Subramaniam Jayanthi, Jean Lud Cadet
Affiliations
Review

Epigenetic landscape of amphetamine and methamphetamine addiction in rodents

Arthur Godino et al. Epigenetics. 2015.

Abstract

Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications-histone acetylation and methylation, DNA methylation-in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome-wide approaches will accelerate the speed of discovery in the field of addiction.

Keywords: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPH, amphetamine; AP1, activator protein 1; ATF2, activating transcription factor 2; BASP1, brain abundant signal protein 1; BDNF, brain derived neurotrophic factor; CCR2, C‒C chemokine receptor 2; CPP, conditioned place preference; CREB, cAMP response element binding protein; ChIP, chromatin immunoprecipitation; CoREST, restrictive element 1 silencing transcription factor corepressor; Cp60, compound 60; DNA methylation; DNMT, DNA methyltransferase; FOS, Finkel–Biskis–Jinkins murine osteosarcoma viral oncogene; GABA, γ-aminobutyric acid; GLUA1, glutamate receptor subunit A1; GLUA2, glutamate receptor subunit A2; GLUN1, glutamate receptor subunit N1; H2Bac, pan-acetylation of histone 2B; H3, histone 3; H3K14Ac, acetylation of histone 3 at lysine 14; H3K18, lysine 18 of histone 3; H3K4, lysine 4 of histone 3; H3K4me3, trimethylation of histone 3 at lysine 4; H3K9, lysine 9 of histone 3; H3K9Ac, acetylation of histone 3 at lysine 9; H3K9me3, trimethylation of histone 3 at lysine 9; H4, histone 4; H4Ac, pan-acetylation of histone 4; H4K12Ac, acetylation of histone 4 at lysine 12; H4K16, lysine 16 of histone 4; H4K5, lysine 5 of histone 4; H4K8, lysine 8 of histone 4; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; HMT, histone methyltransferase; IP, intra-peritoneal; JUN, jun proto-oncogene; KDM, lysine demethylase; KLF10, Kruppel-like factor 10; KMT, lysine methyltransferase; METH, methamphetamine; MeCP2, methyl-CpG binding protein 2; NAc, nucleus accumbens; NMDA, N-methyl-D-aspartate; NaB, sodium butyrate; OfC, orbitofrontal cortex; PfC, prefrontal cortex; REST, restrictive element 1 silencing transcription factor; RNAi, RNA interference; Ser241, serine 241; Sin3A, SIN3 transcription regulator family member A; TSS, transcription start site; VPA, valproic acid; WT1, Wilms tumor protein 1.; amphetamine; histone acetylation; histone methylation; methamphetamine; siRNA, silencing RNA.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Epigenetic desensitization of c-fos after chronic AMPH treatment. Striatal c-fos expression is induced by an acute drug challenge but blunted after chronic AMPH exposure. This transcriptional desensitization correlates with increased binding of ΔfosB and HDAC1 recruitment onto the c-fos promoter. There is coincident increased KMT1A expression after chronic AMPH. Together, these enzymes reshape surrounding chromatin into a repressive conformation for c-fos transcription by catalyzing H4 deacetylation and H3K9 methylation, resulting in blunted c-fos response to acute drug challenge.
Figure 2.
Figure 2.
Chronic METH exposure down-regulates GluA1/A2 and GluN1 expression via diverse epigenetic modifications. In the dorsal striatum, chronic METH exposure allows a MeCP2-independent binding of a CoREST:SIRT2 complex and a MeCP2-dependent recruitment of CoREST, HDAC2 and DNMT1 onto the Upstream Repressive Sequence (URS) of GluA1 and on the promoter of GluA2. Together, these enzymes reshape surrounding chromatin into a repressive conformation for gene transcription by catalyzing H4 deacetylation. GluN1 is downregulated through H4 deacetylation on its promoter mediated by a REST:HDAC1 complex.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Howell LL, Kimmel HL. Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 2008; 75:196-217; PMID:17825265; http://dx.doi.org/10.1016/j.bcp.2007.08.003 - DOI - PubMed
    1. Schultz W. Multiple reward signals in the brain. Nat Rev Neurosci 2000; 1:199-207; PMID:11257908; http://dx.doi.org/10.1038/35044563 - DOI - PubMed
    1. Goodwin JS, Larson GA, Swant J, Sen N, Javitch JA, Zahniser NR, Felice LJD, Khoshbouei H. Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo. J Biol Chem 2009; 284:2978-89; PMID:19047053; http://dx.doi.org/10.1074/jbc.M805298200 - DOI - PMC - PubMed
    1. Cadet JL, Krasnova IN, Jayanthi S, Lyles J. Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox Res 2007; 11:183-202; PMID:17449459; http://dx.doi.org/10.1007/BF03033567 - DOI - PubMed
    1. Bird A. Perceptions of epigenetics. Nature 2007; 447:396-8; PMID:17522671; http://dx.doi.org/10.1038/nature05913 - DOI - PubMed

Publication types

MeSH terms