Addiction to methamphetamine (METH) is a relapsing neuropsychiatric disorder that is secondary, in part, to functional changes in limbic and striatal brain regions (reviewed in Krasnova and Cadet (2009)). Stimulant-induced plastic changes within the striatum are dependent on a series of events that include modifications in the number and subtypes of glutamate receptors (Wolf and Ferrario, 2010). Elucidating the basic mechanisms that maintain METH addiction is important because such an understanding will probably lead to the development of efficacious treatments. The accumulated evidence supports the notion that illicit drugs exert substantial transcriptional and epigenetic changes in the brain (Robison and Nestler, 2011). Gene transcription is regulated by complex epigenetic changes that include post-translational histone modifications and DNA methylation (Mehler, 2008). There is evidence that epigenetic phenomena are intimately involved in the development and the clinical course of complex neuropsychiatric diseases including addiction (Robison and Nestler, 2011). Therefore, we thought it likely that METH might engender transcriptional and epigenetic alterations that are unique to this clinically devastating drug.

As a first step toward clarifying the effects of METH on glutamatergic function, we treated rats with an escalating METH dose paradigm that started at METH (0.5 mg/kg twice/day) and ended with METH (3 mg/kg four times per day) over a period of 2 weeks (McCoy et al., 2011). We found that chronic METH caused significant decreases in mRNA and protein levels of both GluA1 and GluA2 AMPA receptor subunits. We also found that METH caused significant decreases in acetylation of histone H4 at lysine 5 (H4K5), lysine 12 (H4K12), and lysine 16 (H4K16). Using chromatin immunoprecipitation-PCR assay, we found that repeated METH injections produced decreased binding of acetylated H4K5, H4K12, and H4K16 on GluA1 and GluA2 DNA sequences. In addition, chronic METH administration enhanced the recruitment of corepressor of RE1 silencing transcription (CoREST) factor onto GluA1 and GluA2 DNA sequences. METH also caused CoREST co-immunoprecipitation with histone deacetylase 2 (HDAC2) and sirtuin 2 (SIRT2). Moreover, METH increased enrichment of methyl CpG binding protein 2 (MeCP2) on the promoters of both GluA1 and GluA2, with co-immunoprecipitation studies revealing METH-induced MeCP2 interactions with HDAC2. Finally, we demonstrated that the FDA-approved HDAC inhibitor, valproic acid, prevented METH-induced downregulation of GluA1 and GluA2 mRNA levels.

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