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.