Epigenetic therapies and addiction
behaviours, rather than an entire class of enzymes (HDACs), developing a therapeutic to control the morphine-induced alterations in G9a expression is still likely to confer side effects, as G9a has other important roles within neurones which could be jeopardized by interventions. Realistically, a successful epigenetic therapy for morphine addicts would require more precise targeting of the expression of individual genes in order to prevent unwanted side effects. As such, several other studies have focussed on the mechanisms of morphine withdrawal in altering the concentrations of a single protein called brain derived neurotrophic factor (BDNF) in important regions of the brain (Jalali Mashayekhi et al., 2012). BDNF is known to play a crucial role in the formation of memories and learning throughout the brain, thus it is somewhat unsurprising that it is suspected to contribute to the development of addictive
behaviours (Miranda et al., 2019; Barker et al., 2015). Researchers studying the protein in rats found that by consistently providing them with morphine, the relative levels of BDNF in the ventral tegmental area (a region of the brain involved in both reward and motivation) remained mostly unchanged, but after a prolonged period (seven days) without receiving the drug, BDNF levels in this region began
Figure 4 – Visual depiction of how withdrawal from morphine causes demethylation of the histones surrounding the BDNF promoter region, causing overexpression of BDNF to occur. The presence of repressive methyl groups on histones (left) causes the expression of BDNF to be tightly controlled and regulated. Upon abstinence from morphine, however, epigenetic pathways are triggered which demethylate the histones (right), causing abnormal expression of BDNF.
to markedly increase. Upon studying the brains of the rats, the researchers discovered that this increased expression of the protein was due to the way in which morphine interacts with epigenetic enzymes, causing demethylation of histones associated with BDNF’s promote r region (thus leading to increased gene expression) during withdrawal (Figure 4). If a potential therapeutic were to target this pathway of addiction, one would expect a drug to selectively remethylate histones in the BDNF promoter region, returning BDNF expression to naturally regulated levels. However, a major issue with this is that several different animal models have demonstrated that the ‘ deprivation of BDNF . . . results in severe impairment of learning and memory’ (Yamada, Mizuno and Nabeshima, 20 02), posing a clear risk if the therapeutic were to overcompensate and shut down BDNF production altogether; artificially decreasing the activity of an essential protein in the brain may have severe consequences which may actually worsen a patient’s condit ion. On top of this, the overwhelming majority of research into BDNF- based therapies has so far focussed on increasing the levels of BDNF, rather than limiting its presence, suggesting that this form of treatment may be unrealistic (Miranda-Lourenço et al., 2020). Nonetheless, there is still potential for other individual genes to be targeted by epigenetic therapies. For example, numerous studies have so far found that chronic exposure to morphine leads to persistent overexpression of a key transcription factor know n as ΔFosB, leading to markedly increased brain plasticity and addictive tendencies in mice (Robison and Nestler, 2011; Hamilton et al., 2017). If a
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