Нарушение экспрессии мРНК мю- и каппа-опиоидных рецепторов в среднем мозге крыс с пренатальной алкогольной интоксикацией

Нарушение эпигенетического репрограммирования под действием экзогенных факторов в пренатальном периоде отражается на развитии и формировании фенотипа взрослого организма. Один из таких факторов – алкоголь, воздействие которого в период пренатального онтогенеза может приводить к высокому риску злоупотребления алкоголем в будущем. Механизмы, лежащие в основе этого эффекта, в настоящее время мало изучены. Мы предполагаем, что изменение «подкрепляющего» действия алкоголя в результате пренатальной алкоголизации может быть связано с нарушением транскрипционной активности генов опиоидной системы мозга. В работе проведён сравнительный анализ добровольного потребления алкоголя и уровня экспрессии мРНК μ- (MOP) и κ-опиоидных (KOP) рецепторов в мезолимбических областях мозга взрослых крыс-самцов Wistar (PND60) – потомков самок, потреблявших 10%-ный р-р этанола со 2-го по 21-й дни беременности, и контрольных животных. Пренатально алкоголизированные крысы отличались от контрольных высоким предпочтением алкоголя и низким уровнем экспрессии мРНК MOР и KOР в среднем мозге. Выявленные нарушения могут лежать в основе дисфункции опиатной системы и, как следствие, высокого риска формирования аддиктивного поведения во взрослом возрасте.

1. Al-Hasani R., Bruchas M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363–1381. DOI: 10.1097/ALN.0b013e318238bba6.

2. Alati R., Al Mamun A., Williams G.M., O’Callaghan M., Najman J.M., Bor W. In utero alcohol exposure and prediction of alcohol disorders in early adulthood: A birth cohort study. Arch. Gen. Psychiatry. 2006;63(9):1009–1016. DOI: 10.1001/archpsyc.63.9.1009.

3. Allan A.M., Chynoweth J., Tyler L.A., Caldwell K.K. A mouse model of prenatal ethanol exposure using a voluntary drinking paradigm. Alcohol. Clin. Exp. Res. 2003;27(12):2009–2016. DOI: 10.1097/01.ALC.0000100940.95053.72.

4. Baer J.S., Sampson P.D., Barr H.M., Connor P.D., Streissguth A.P. A 21-year longitudinal analysis of the effects of prenatal alcohol exposure on young adult drinking. Arch. Gen. Psychiatry. 2003;60(4):377–385. DOI: 10.1001/archpsyc.60.4.377.

5. Basavarajappa B.S., Subbanna S. Epigenetic mechanisms in developmental alcohol-induced neurobehavioral deficits. Brain Sci. 2016;6(2):12. DOI: 10.3390/brainsci6020012.

6. Bazov I., Sarkisyan D., Kononenko O., Watanabe H., Taqi M.M., Stålhandske L., Verbeek D.S., Mulder J., Rajkowska G., Sheedy D., Kril J., Sun X., Syvänen A.C., Yakovleva T., Bakalkin G. Neuronal expression of opioid gene is controlled by dual epigenetic and transcriptional mechanism in human brain. Cereb. Cortex. 2018;28(9):3129–3142. DOI: 10.1093/cercor/bhx181.

7. Berrettini W. Alcohol addiction and the mu-opioid receptor. Prog. Neuro-psychopharmacol. Biol. Psychiatry. 2016;65:228–233. DOI: 10.1016/j.pnpbp.2015.07.011.

8. Estave P.M., Spodnick M.B., Karkhanis A.N. KOR control over addiction processing: An exploration of the mesolimbic dopamine pathway. Handb. Exp. Pharmacol. 2022;271:351–377. DOI: 10.1007/164_2020_421.

9. Ford C.P., Mark G.P., Williams J.T. Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location. J. Neurosci. 2006;26(10):2788–2797. DOI: 10.1523/JNEUROSCI.4331-05.2006.

10. Fricker L.D., Margolis E.B., Gomes I., Devi L.A. Five decades of research on opioid peptides: Current knowledge and unanswered questions. Mol. Pharmacol. 2020;98(2):96–108. DOI: 10.1124/mol.120.119388.

11. Green A.S., Grahame N.J. Ethanol drinking in rodents: Is free-choice drinking related to the reinforcing effects of ethanol? Alcohol. 2008;42(1):1–11. DOI: 10.1016/j.alcohol.2007.10.005.

12. Hao J., Hao W., Liu Z., Shi P. The toggle switch model for gene expression change during the prenatal-topostnatal transition in mammals. Mol. Biol. Evol. 2022;39(3):msac036. DOI: 10.1093/molbev/msac036.

13. Hutsell B.A., Cheng K., Rice K.C., Negus S.S., Banks M.L. Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine versus food choice and extended-access cocaine intake in rhesus monkeys. Addict. Biol. 2016;21(2):360–373. DOI: 10.1111/adb.12206.

14. Koob G.F. Addiction is a reward deficit and stress surfeit disorder. Front. Psychiatry. 2013;4:72. DOI: 10.3389/fpsyt.2013.00072.

15. Koob G.F., Volkow N.D. Neurobiology of addiction: A neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–773. DOI: 10.1016/S2215-0366(16)00104-8.

16. Lalanne L., Ayranci G., Kieffer B.L., Lutz P.E. The kappa opioid receptor: From addiction to depression, and back. Front. Psychiatry. 2014;5:170. DOI: 10.3389/fpsyt.2014.00170.

17. Laurent V., Leung B., Maidment N., Balleine B.W. μ- and δ-opioid-related processes in the accumbens core and shell differentially mediate the influence of reward-guided and stimulus-guided decisions on choice. J. Neurosci. 2012;32(5):1875–1883. DOI: 10.1523/JNEUROSCI.4688-11.2012.

18. Lussier A.A., Morin A.M., MacIsaac J.L., Salmon J., Weinberg J., Reynolds J.N., Pavlidis P, Chudley A.E., Kobor M.S. DNA methylation as a predictor of fetal alcohol spectrum disorder. Clin. Epigenetics. 2018;10:5. DOI: 10.1186/s13148-018-0439-6.

19. MacPherson L., Magidson J.F., Reynolds E.K., Kahler C.W., Lejuez C.W. Changes in sensation seeking and risk-taking propensity predict increases in alcohol use among early adolescents. Alcohol. Clin. Exp. Res. 2010;34(8):1400–1408. DOI: 10.1111/j.1530-0277.2010.01223.x.

20. Mandal C., Halder D., Jung K.H., Chai Y.G. Gestational alcohol exposure altered DNA methylation status in the developing fetus. Int. J. Mol. Sci. 2017;18(7):1386. DOI: 10.3390/ijms18071386.

21. Margolis E.B., Lock H., Chefer V.I., Shippenberg T.S., Hjelmstad G.O., Fields H.L. Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc. Natl Acad. Sci. USA. 2006;103(8):2938–2942. DOI: 10.1073/pnas.0511159103.

22. Marjonen H., Sierra A., Nyman A., Rogojin V., Grohn O., Linden A.M., Hautaniemi S., Kaminen-Ahola N. Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model. PloS One. 2015;10(5):e0124931. DOI: 10.1371/journal.pone.0124931.

23. McQuire C., Mukherjee R., Hurt L., Higgins A., Greene G., Farewell D., Kemp A., Paranjothy S. Screening prevalence of fetal alcohol spectrum disorders in a region of the United Kingdom: A population-based birth-cohort study. Prev. Med. 2019;118:344–351. DOI: 10.1016/j.ypmed.2018.10.013.

24. Miao Z., Li Y., Mao F., Zhang J., Sun Z.S., Wang Y. Prenatal witness stress induces intergenerational anxiety-like behaviors and altered gene expression profiles in male mice. Neuropharmacology. 2022;202:108857. DOI: 10.1016/j.neuropharm.2021.108857.

25. Molina J.C., Spear N.E., Spear L.P., Mennella J.A., Lewis M.J. The International society for developmental psychobiology 39th annual meeting symposium: Alcohol and development: Beyond fetal alcohol syndrome. Dev. Psychobiol. 2007;49(3):227–242. DOI: 10.1002/dev.20224.

26. Nizhnikov M.E., Pautassi R.M., Carter J.M., Landin J.D., Varlinskaya E.I., Bordner K.A., Werner D.F., Spear NE. Brief prenatal ethanol exposure alters behavioral sensitivity to the kappa opioid receptor agonist (U62,066E) and antagonist (Nor-BNI) and reduces kappa opioid receptor expression. Alcohol. Clin. Exp. Res. 2014;38(6):1630–1638. DOI: 10.1111/acer.12416.

27. Pautassi R.M., Nizhnikov M.E., Acevedo M.B., Spear N.E. Early role of the kappa opioid receptor in ethanol-induced reinforcement. Physiol. Behav. 2012;105(5):1231–1241. DOI: 10.1016/j.physbeh.2012.01.003.

28. Popova S., Lange S., Probst C., Gmel G., Rehm J. Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: A systematic review and metaanalysis. Lancet Glob. Health. 2017;5(3):e290–e299. DOI: 10.1016/S2214-109X(17)30021-9.

29. Shippenberg T.S., Zapata A., Chefer V.I. Dynorphin and the pathophysiology of drug addiction. Pharmacol. Ther. 2007;116(2):306–321. DOI: 10.1016/j.pharmthera.2007.06.011.

30. Spear N.E., Molina J.C. Fetal or infantile exposure to ethanol promotes ethanol ingestion in adolescence and adulthood: A theoretical review. Alcohol. Clin. Exp. Res. 2005;29(6):909–929. DOI: 10.1097/01.alc.0000171046.78556.66.

31. Streissguth A.P., Bookstein F.L., Barr H.M., Sampson P.D., O’Malley K., Young J.K. Risk factors for adverse life outcomes in fetal alcohol syndrome and fetal alcohol effects. J. Dev. Behav. Pediatr. 2004;25(4):228–238. DOI: 10.1097/00004703-200408000-00002.

32. Tejeda H.A., Bonci A. Dynorphin/kappa-opioid receptor control of dopamine dynamics: Implications for negative affective states and psychiatric disorders. Brain Res. 2019;1713:91–101. DOI: 10.1016/j.brainres.2018.09.023.

33. Trevisani M., Smart D., Gunthorpe M.J., Tognetto M., Barbieri M., Campi B., Amadesi S., Gray J., Jerman J.C., Brough S.J., Owen D., Smith G.D., Randall A.D., Harrison S., Bianchi A., Davis J.B., Geppetti P. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat. Neurosci. 2002;5(6):546–551. DOI: 10.1038/nn0602-852.

34. Youngentob S.L., Glendinning J.I. Fetal ethanol exposure increases ethanol intake by making it smell and taste better. Proc. Natl Acad. Sci. USA. 2009;106(13):5359–5364. DOI: 10.1073/pnas.0809804106.

35. Youngentob S.L., Kent P.F., Sheehe P.R., Molina J.C., Spear N.E., Youngentob L.M. Experience-induced fetal plasticity: The effect of gestational ethanol exposure on the behavioral and neurophysiologicolfactory response to ethanol odor in early postnatal and adult rats. Behav. Neurosci. 2007;121(6):1293–1305. DOI: 10.1037/0735-7044.121.6.1293.

36. Youngentob S.L., Molina J.C., Spear N.E., Youngentob L.M. The effect of gestational ethanol exposure on voluntary ethanol intake in early postnatal and adult rats. Behavi. Neurosci. 2007;121(6):1306–1315. DOI: 10.1037/0735-7044.121.6.1306.

37. Zuccarello D., Sorrentino U., Brasson V., Marin L., Piccolo C., Capalbo A., Andrisani A., Cassina M. Epigenetics of pregnancy: Looking beyond the DNA code. J. Assist. Reprod. Genet. 2022;39(4):801–816. DOI: 10.1007/s10815-022-02451-x.