Rachael Wong

Introduction. Cocaine use disorder is 79% heritable, and 2 million Americans use cocaine monthly with over 850,000 of them meeting the DSM-V criteria for cocaine dependence.^5,9 While identification of specific genetic factors and pharmacological treatment has remained elusive, promising results are arising from the study of epigenetic modifications by DNA methylation in the development of cocaine addiction behaviors.^1,5 During DNA methylation, DNA methyltransferases (Dnmt) add a methyl group from S-adenosyl-L-methionine to the fifth position of cytosine and Tet enzymes cause demethylation by hydroxylating that methyl group.²  Methods. Rodent models were used to study alteration in behavior and gene expression after cocaine administration. Certain groups were given either a saline, acute cocaine, repeat saline, or repeat cocaine treatment.^2,7 Others underwent cocaine self-administration training to nose-poke an active hole for cocaine.^3,4,9 The brain was dissected out, and qRT-PCR was used to measure the level of gene expression of Dnmt and Tet enzymes.^2-4 Recombinant adeno-associated viruses were used to deliver shRNA sequences that downregulate specific enzymes.  Results. Both the NAc and peripheral blood cells (PBC) demonstrated biphasic Dnmt patterns, which means that transcription levels drop within the first 3 hours after acute cocaine injection and increase at 24 hours.² The NAc also showed significantly reduced Tet1/2 levels, and overexpression of Tet1 caused a reduction in cocaine seeking behavior.^1-2 Dnmt3a2 was specifically elevated in the NAc shell during cue-induced reinstatement, and drove incubation of cocaine craving by upregulating plasticity related genes such as Egr2, Arc, and FosB.³ However, reduction of Dnmt3a in the NAc caused a compensatory elevation in Dnmt3b which actually increased behavioral sensitization.⁷ Altered methylation patterns also occur in the hippocampus, prefrontal cortex, and cerebellum.^2,4   Conclusions. Changes in DNA methylation patterns in the brain because of cocaine use disorder causes significant dysregulation of RNA transcription which induces plasticity mechanisms that result in cocaine addiction behaviors.⁸ Similar methylation patterns between the PBC and NAc indicate that PBC may be a potentially more accessible biomarker to identify cocaine addiction.² Based on the current progress made on DNA methylation, a few potential avenues of treatment can be identified including systemic injections of methyl supplementation by L-methionine, selective reduction of Dnmt3a2 in the NAc shell during withdrawal, and overexpressing Tet in the NAc.^3,4,9 However, more research is needed to elucidate the specific pathway by which these epigenetic modifications occur, to translate these correlations to humans, and to assess the best therapeutic treatment.

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