Methadone is a synthetic opioid most commonly applied for the treatment of opiate addiction. Methadone maintenance therapy is used to control opioid dependence and prevent withdrawal symptoms. However, chronic exposure to opioids and/or long-term maintenance therapy can lead to persistent changes in brain gene expression and neural plasticity. There are some indications that opioid-induced epigenetic variations can play an important role in opiate addiction, but there is no information about the possible involvement of these processes during withdrawal. This project will characterize global epigenetic changes at the DNA level (methylation and hydroxymethylation of cytosine) and changes in the expression of transcription factors possibly playing a role in drug abuse (e.g., CREB, Fos, MeCP2). A special attention will be paid to the methylation of the gene and transcript for brain-derived neurotrophic factor which is apparently involved in the development of persistent neuroadaptation processes and behavioral changes during addiction. The impact of methadone will be investigated in selected brain regions (prefrontal cortex, hippocampus, striatum, and cerebellum) of rats exposed to increasing doses of the drug for 10 days and subsequently withdrawn for different time periods. Besides analyzing the expression levels and possible modifications of selected proteins, animal anxiety- and depression-like behaviour will also be monitored. The results of this project can advance our understanding of the opioid-induced changes in the epigenetic and epitranscriptional landscapes and their interplay in drug addiction.


Five relevant publications of the research group:

Pacesova D., Volfova B., Cervena K., Hejnova L., Novotny J. and Bendova Z. (2015) Acute morphine affects the rat circadian clock via rhythms of physphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus. Br. J. Pharmacol. 172:3638-3649.

Hejnova L., Skrabalova J. and Novotny J. (2017) Prolonged morphine treatment alters expression and plasma membrane distribution of β-adrenergic receptors and some other components of their signaling system in rat cerebral cortex. J. Mol. Neurosci. 63:364-376.

Skrabalova J., Karlovska I., Hejnova L. and Novotny J. (2018) Protective effect of morphine against the oxidant-induced injury in H9c2 cells. Cardiovasc. Toxicol. 18:374-385.

Melkes B., Markova V., Hejnova L. and Novotny J. (2020) β-Arrestin 2 and ERK1/2 are important mediators engaged in close cooperation between TRPV1 and µ-opioid receptors in the plasma membrane. Int. J. Mol. Sci. 21:4626.

Bendova Z., Pacesova D. and Novotny J. (2020) The day-night differences in ERK1/2, GSK3β activity and c-Fos levels in the brain, and the responsiveness of various brain structures to morphine. J. Comp. Neurol. 528:2471-2495.

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