ON THE QUESTION OF ADENOSINE SYSTEM PARTICIPATION IN THE PATHOGENESIS OF NEUROSES

Lutsenko R. V

LITERATURE REVIEWS

Scentific article

The analysis of main links of the pathogenesis of anxiety disorders and ways of correcting this pathology remains one of the most urgent problems today, since the frequency and prevalence of mental pathology is constantly increasing. Attention is drawn to the adenosine system of the brain, which is represented by the amygdala, prefrontal cortex, hippocampus, thalamus, and other structures and is responsible for feelings of fear/anxiety and other behavioral responses. Adenosine regulates the release of other neurotransmitters and the functioning of ion channels. A1 autoreceptors in CNS neurons mediate inhibition of the mediator release. Postsynaptic A1 receptors regulate the functioning of potassium channels and excitability. A2A receptors are associated with other neurotransmitters, in particular in the striatum, which is one of the centers in the formation of neurotic pathology. Adenosine and A-receptor agonists have been found to have an anxiolytic effect in neuroethological tests, while antagonists have the opposite effect. The involvement of the adenosine system in anxiogenesis was confirmed in A2A receptor gene knockout mice. It has been shown that these effects may be due to activation of caspase-1 and increased release of interleukin IL-1β, which is associated with A2A receptors. The involvement of the adenosine system in the progression of anxiety disorders is confirmed by the information that positive allosteric modulators exert pronounced anxiolytic effects similar to diazepam. A2A receptors should not be considered as targets for the action of anxiolytics due to the insufficient experimental basis and the low expression of these receptors in the areas of the brain responsible for the state of anxiety. A1A receptors are the target for the correction of anxiety pathology, since their stimulation regulates the activity of neurons by inhibiting the release of other neurotransmitters. A1A-receptor agonists have been positioned as agents with the great therapeutic potential, however, they are poorly selective and their clinical use may cause significant adverse reactions. A1 -receptor agonists, the effects of which are dosedependent, have been synthesized and studied. Herbal adenosinotropic agents can also have therapeutic potential for neuroses.

neurosis,anxiety,adenosine,adenosine receptor,adenosine receptor agonist.

1. Shafranskyi VV, Dudnyk SV. Psykhichne zdorovia naselennia Ukrainy stan, problemy ta shliakhy vyrishennia. Ukraina, zdorovia natsii. 2016;(39):12-8. [in Ukrainian].
2. Iurieva LM. Analiz fenomeniv tryvohy ta depresii u pershi tyzhni viiny henderno-vikovi aspekty. NeiroNEWS©. 2022;3-4(134):28-31. [in Ukrainian].
3. Fan J, Guanghao Y, Wei Y, Modi Y, Shuohui G, Jiayin L, et al. Stress in regulation of GABA amygdala system and relevance to neuropsychiatric diseases. Front. Neurosci. 2018 Aug 14;12:562. DOI: 10.3389/fnins.2018.00562.
4. Nuss P. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis. Treat. 2015 Jan 17;11:165-75. DOI: 10.2147/NDT.S58841.
5. Hofer M, Dusek L, Hoferova Z, Stixova L, Pospisil M. Expression of mRNA for Adenosine A1, A2a, A2b, and A3-receptors in HL–60 Cells: Dependence on Cell Cycle Phases. Physiol. Res. 2011;60:913-20. DOI: doi.org/10.33549/physiolres. 932233.
6. Jacobson KA, Merighi S, Varani K, Borea PA, Baraldi S, Tabrizi MA, et al. A3 adenosine receptors as modulators of inflammation: from medicinal chemistry to therapy. Med. Res. Rev. 2018 Jul;38(4):1031-72. DOI: 10.1002/med.21456.
7. Asatryan L, Nam HW, Lee MR, Thakkar MM, Dar MS, Davies DL, et al. Implication of the purinergic system in I alcohol use Disorder. Alcohol Clin Exp Res. 2011. 35:584-594. DOI: 10.1111/j.1530-0277.2010.01379.
8. Hines DJ, Haydon PG. Astrocytic adenosine from synapses to psychiatric disorders. Philos Trans R. Soc Lond B Biol Sci. 2014;369:1654. DOI: 10.1098/rstb.2013.0594.
9. Freitag CM. Genetics of autistic disorders: review and clinical implications. Eur. Child Adolesc Psychiatry. 2010;19:169-78. DOI: 10.1007/ s00787-009-0076-x.
10. Okuyama E, Ebihara H, Takeuchi H, Yamazaki M. Adenosine the anxiolytic–like principle of the Arillus of Euphoria longana. Planta Medica. 1999 Feb 2;65:115-9. DOI: 10.1055/s-1999-14055.
11. Yamada K, Kobayashi M, Kanda T. Chapter Fifteen-Involvement of adenosine A2A receptors in depression and anxiety. Academic Press: Cambridge, MA. 2014;119:373-93.
12. Shen HY, Chen JF. Adenosine A2-receptor in Psychopharmacology: Modulators of Behavior, Mood and Cognition Current. Neuropharmacology. 2009;7:195-206. DOI: 10.2174/157015909789152191.
13. Prediger RD, Batista LC, Takahashi RN. Adenosine A1-receptors modulate the anxiolytic–like effect of ethanol in the elevated plus–maze in mice. Eur. J. Pharmacol. 2004;499:147-54. DOI: 10.1016/j.ejphar.2004.07.106.
14. Hai-Ying S, Jiang-Fan Ch. Adenosine A2-receptor in psychopharmacology: modulators of behavior, mood and cognition current. Neuropharmacology. 2009 Sep;7(3):195-206. DOI: 10.2174/157015909789152191.
15. Lara DR. Caffeine, mental health, and psychiatric disorders. Journal of Alzheimers Disorder. 2010;20(1):239-48. DOI: 10.3233/JAD-2010- 1378.
16. Liu W, Yang Z-l, Zhou L, Li X, Yan F, Guan L, et al. Morphine treatment enhances extracellular ATP enzymolysis and adenosine generation in rat astrocytes. Sheng Li Xue Bao. 2011;63:20-4.
17. Giménez-Llort L, Schiffmann SN, Shmidt T, Canela L, Camón L, Wassholm M, et al. Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain. Neurobiology of Learning and Memory. 2007 Jan;87(1):42-56. DOI: 10.1016/j. nlm.2006.05.004.
18. Zangrossi HJr, Leite JR, Graef FG. Anxiolytic effect of carbamazepine in the elevated plus–maze: possible role of adenosine. Psychopharmacology. 1992 Jan;106(1):85-9. DOI: 10.1007/BF02253593.
19. Cheng JP, Hoffman AN, Zafonte RD, Kline AE. A delayed and chronic treatment regimen with the 5–HT1A-receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning. Behav. Brain Res. 2008 Jan;194(1):79-85. DOI: 10.1016/jbbr.2008.06.025.
20. Miyamoto С, Yoshida M, Yoshikawa M, Mizushige T, Ohinata K. Complement C5a exhibits anxiolytic–like activity via the prostaglandin D2–DP1 receptor system coupled to adenosine A2A and GABAA-receptors. Prostaglandins Other Lipid Mediat. 2012 May;98(1-2):17-22. DOI: 10.1016/j.prostaglandins. 2012.03.004.
21. Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde К. Efficacy of selective serotonin reuptake inhibitors and adverse events: metaregression and mediation analysis of placebo-controlled trials. Br. J. Psychiatry 2016 Feb;208(2):114-9. DOI: 10.1192/bjp.bp.114.150136.
22. Coelho JE, Alves P, Canas PM, Valadas JS, Shmidt T, Batalha VL, et al. Overexpression of adenosine A2A-receptors in rats: Effects on Depression, Locomotion, and Anxiety. Front. Psychiatry. 2014 Jun 13;5:67. DOI: 10.3389/ fpsyt.2014.00067.
23. Huang Z, Liu R, Bai X, Zhao G, Song J, Wu S et al. Protective Effects of the Novel Adenosine Derivative WS0701 in a Mouse Model of Posttraumatic Stress Disorder. Acta Pharmacol. Sin. 2014 Jan;35(1):24-32. DOI: 10.1038/aps. 2013.143.
24. Wei CJ, Augusto E, Gomes CA, Singer P, Wang Y, Boison D, et al. Regulation of fear responses by striatal and extrastriatal adenosine A2A-receptors in forebrain. Biol. Psychiatry. 2014 Jun 1;75(11):855-863. DOI: 10.1016/j. biopsych.2013.05.003.
25. Hohoff Ch, Mullings EL, Heatherley SV, Freitag ChM, Neumann LC, Domschke K, et al. Adenosine A2A-receptor gene: evidence for association of risk variants with panic disorder and anxious personality. J. Psychiatr. Res. 2010 Oct;44(14):930-7. DOI: 10.1016/j. jpsychires.2010.02.006.
26. Chiu GS, Darmody PT, Walsh JP, Moon ML, Kwakwa KA, Bray JK, et al. Adenosine through the A2A-adenosine receptor increases IL-1β in the brain contributing to anxiety. Behav. Immun. 2014 Oct;41:218-31. DOI: 10.1016/j.bbi. 2014.05.018.
27. Caetano L, Pinheiro H, Patrício P, Mateus-Pinheiro A, Alves ND, Coimbra B. Adenosine A2A-receptor regulation of microglia morphological remodeling-gender bias in physiology and in a model of chronic anxiety. Mol. Psychiatry. 2017 Jul;22(7):1035-1043. DOI: 10.1038/ mp.2016.173.
28. Caetano L, Pinheiro H, Patrício P, Mateus-Pinheiro A, Alves ND, Coimbra B, et al. Adenosine receptor as drug targets-what are the challenger? Nat. Rev. Drug Discov. 2013 Apr;12(4):265-86. DOI: 10.1038/nrd3955.
29. Serchov T, Clement H-W, Schwarz MK, Iasevoli F, Tosh DK, Idzko M, et al. Increased signaling via adenosine A1-receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of homer1a. Neuron. 2015 Aug 5;87(3):549-62. DOI: 10.1016/j.neuron. 2015.07.010.
30. Giménez-Llort L, Fernández-Teruel A, Escorihuela RM, Fredholm BB, Tobeña A, Pekny M, et al. Mice lacking the adenosine A1-receptor are anxious and aggressive, but are normal learners with reduced muscle strength and survival rate. Eur. J. Neurosci. 2002 Aug;16(3):547- 50. DOI: 10.1046/j.1460-9568.2002.02122.x.
31. Romagnoli R, Baraldi PG, Tabrizi MA, Gessi S, Borea PA, Merighi S. Allosteric enhancers of A1-adenosine receptors: state of the art and new horizons for drug development. Med. Chem. 2010;17(30):3488-502. DOI: 10.2174/09298 6710792927831.
32. Romagnoli R, Baraldi PG, Jzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC, et al. Synthesis and biological evaluation of novel allosteric enhancers of the A1-adenosine erceptor based on 2-amino-3-(40-chlorobenzoyl)-4-substituted-5-arylethynyl hiopthene. J. Med. Chem. 2014 Sep 25;57(18):7673-86. DOI: 10.1021/jm5008853.
33. Vincenzi F, Targa M, Romagnoli R, Merighi S, Gessi S, Baraldi PG. TRR469, a Potent A1 Adeno-sine Receptor Allosteric Modulator, Exhibits Anti-Nociceptive Properties in Acute and Neuropathic Pain Models in Mice. Neuropharmacology. 2014 Jun;81:6-14. DOI: 10.1016/j. neuropharm.2014. 01.028.
34. Marek GJ. Activation of adenosine 1 receptors induces antidepressant–like, antiimpulsive effects on differential reinforcement of low-rate 72-s behavior in rats. J pharmacol exp ther. 2012 May;341(2):564-70. DOI: 10.1124/ jpet.112.191718.
35. Paul S, Elsinga PH, Ishiwata K, Dierckx RAJO, Waarde A. Adenosine A1-receptors in the central nervous system: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging. Current Medicinal Chemistry. 2011;18(31):4820-35. DOI: 10.2174/092986711797535335.
36. Nenajdenko V. Isocyanide Chemistry. Weinheim: Wiley-VCH VeriagGmbH Co. KCaA; 2012. 606 р.
37. Koetter U, Barrett M, Lacher S, Abdelrahman A, Dolnick D. Interactions of Magnolia and Ziziphus extracts with selected central nervous system receptors. J. Ethnopharmacol. 2009 Jul 30;124(3):421-5. DOI: 10.1016/j. jep.2009. 05.040.
38. Pasquini S, Contri Ch, Merighi S, Gessi S, Borea PA, Varani K. Adenosine receptors in neuropsychiatric disorders; fine regulators of neurotransmission and potential therapeutic targets. International Journal of molecular sciences. 2022 Jan 22;23(3):1219. DOI: 10.3390/ ijms23031219.

«Bulletin of problems biology and medicine» Issue 4 (167), 2022 year, 76-83 pages, index UDK 616.8-00-092

10.29254/2077-4214-2022-4-167-76-83