Shalin Shah

Introduction. Methamphetamine addiction is a neuropsychiatric disorder characterized by repeated methamphetamine exposure and subsequent behavioral changes caused by underlying neuroadaptations at the molecular, cellular, and tissular level in the brain’s reward pathway. Epigenetic mechanisms have emerged as a key area of research to explain how these long-lasting neuroadaptations develop and explain the transition from recreational methamphetamine use to addiction¹. Studies have found that drug induced histone modifications, such as acetylation and methylation, play an important role in promoting or repressing gene expression^{2, 3}. These findings are important because they suggest that particular signaling mechanisms controlling histone acetylation and methylation could serve as potential pharmacologic targets to inhibit methamphetamine addiction. Methods: Rodent models where utilized and experimental groups were divided between control groups and methamphetamine treatment groups to study genes coding for certain types of histone proteins involved in histone acetylation and methylation. RNA was isolated and chromatin immunoprecipitation sequencing was subsequently performed. This was followed by PCR and statistical analyses that indicated significant differences in expression of various types of histone modifying proteins^1-4. Results: Rats in the methamphetamine treatment groups across various experiments showed significant differences in histone protein expression in comparison to control groups in several areas of neural tissue involved in the mesolimbic reward pathways. In the rat dorsal striatum, acute methamphetamine injections caused expression of genes that increased binding of an acetylated histone protein, H4K5Ac². Another study found that in the rat medial prefrontal cortex, methamphetamine treated mice had decreased overall levels of acetylated H3 and H4, which are two types of histone proteins involved in the structure of chromatin eukaryotic cells⁴. Hypoacetylation of H4 was found to induce decreased striatal glutamate receptor expression: GluA1 and GluA2 AMPAR subunits and GluN1 NMDAR subunits⁵. In the nucleus accumbens, methamphetamine exposed rats showed high expression of several types of histone deacetylation proteins: HDAC1, HDAC3, HDAC8⁶. Knockdown of histone methylation enzymes, such as MII1 and Kdm5c, were found to be associated with methylation changes that disrupted methamphetamine associated memory³. Conclusions: The results of these studies are significant because they provide insight into potential targets for pharmacologic intervention that could disrupt the development of methamphetamine addiction. Disrupting expression of histone modifying enzymes associated with methamphetamine addiction in the different regions of the mesolimbic reward pathway, such as HDAC1, HDAC3, HDAC8, MII1, Kdm5c, and H4K5Ac holds promise as potential treatment options, but more research into specific sequencing mechanisms is necessary to further understand how to treat methamphetamine addiction^1-6.

1. Godino A, Jayanthi S, Cadet JL. Epigenetic landscape of amphetamine and methamphetamine addiction in rodents. Epigenetics. 2015:10(7):574-580.
2. Cadet JL, Jayanthi S, McCoy MT, et al. Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum.
3. Aguillar-Valles A, Vaissiere T, Griggs EM, et al. Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation. Biological Psychiatry. 2014:76(1):57-65.
4. Gonzalez B, Jayanthi S, Gomez N, et al. Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex. Progress in Neuro-psychopharmacology and Biological Psychiatry. 2018: 82:1-11.
5. Jayanthi S, McCoy MT, Chen B, et al. Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms. Biological Psychiatry. 2014: 76(1):47-56.
6. Cadet JL, Ladenheim B, Krasnova IN, Jayanthi S. Differential expression of mRNAs coding for histone deacetylases (HDACs) in the nucleus accumbens of compulsive methamphetamine takers and abstinent rats. Journal of Drug and Alcohol Research. 2016:5:1-9.