Epigenetic therapies and addiction
synaptic plasticity’ (Kim et al., 2012). The same study also found that in morphine-treated neurones, enzymes HDAC6 and HDAC7 were also upregulated, whilst HDAC5, on the other hand, was downregulated (Figure 2) (Doke, Pendyala and Samikkannu, 2021). Together, these findings suggest that these HDAC enzymes would make ideal targets for therapeutics; in fact, it had already been shown several years prior that ‘repeated [pre - treatment] with HDAC inhibitors . . . [was] able to attenuate the development of sensitization to morphine’ in mice (Jing et al., 2011). This was then supported by two later studies which showed that administering HDAC inhibitors alongside injections of morphine or during abstinence from morphine can also cause tangible reductions in the
Figure 2 – Visualization of the effects that morphine has on the regulation of several HDAC epigenetic enzymes (top), where green arrows represent an increase in enzyme expression and red arrows represent a decrease in enzyme expression. Shown at the bottom is the way in which a therapeutic might counter the effects of morphine by correcting changes in enzyme regulation.
withdrawal symptoms experienced by morphine-addicted mice (Rehni et al., 2012; Wang et al., 2014). So far, the research into HDAC inhibitors as potential rehabilitative treatments for morphine addiction seem promising. However, the side effects associated with these inhibitors as a result of preventing HDACs from carrying out other necessary epigenetic alterations throughout the brain can be severe, meaning that they are typically only a justifiable treatment option in terminally ill patients (Carey, 2011). Fundamentally, there is unlikely to be any way in which the side effects caused by HDAC inhibition can be mitigated, thus targeting these enzymes as therapeutic targets would not be desirable for clinical development.
Similar to findings with HDACs, another study (Sun et al., 2012) found that chronic exposure to morphine in mice caused altered activity of G9a, a different epigenetic enzyme which represses the expression of particular genes by attaching methyl groups to nearby histones. Morphine was found to selectively reduce the activity of G9a, resulting in fewer repressive gene modifications (Figure 3), particularly in genes belonging to the glutamate signalling pathways of the nucleus accumbens (NAc), a region of the brain involved in various ‘reward’ systems (W alker and Nestler, 2018). Prior
Figure 3 – Visual depiction of the role of morphine in upregulating the glutamatergic system by reducing the activity of G9a, a histone methyltransferase enzyme.
to this 2012 study, it had already been shown that changes in glutamate signalling in the NAc were partly responsible for the development of morphine addiction (Siggins et al., 2006), and the epigenetics that cause these alt erations are now better understood; morphine’s alterations in G9a activity cause an increase in the expression of glutamate receptors grin2a , grip1 , grm5 and grm8 , most likely increasing the sensitivity of the NAc to glutamate signalling and thus contribut ing to the observed ‘abnormal [behavioural] adaptations’ (Sun et al., 2012). While this study differs to previous studies in the sense that only a single epigenetic enzyme, G9a, is implicated in this pathway that leads to addictive
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