AMİTRİPTİLİNİN FAREDEKİ ANTİDEPRESAN BENZERİ ETKİSİNİN ADENOZİN A2A RESEPTÖR ANTAGONİZMASI İLE ARTIŞI

Year 2018, Volume: 27 Issue: 3, 205 - 210, 25.12.2018

Gülay Sezer

Abstract

Amaç: Antidepresan bir ilaç olan amitriptilinin
periferal etkilerinde adenozinerjik sistemin rolü olduğu
ağrı modellerinde ve amitriptilinin neden olduğu
kardiyovasküler sistem toksisitesinde gösterilmiştir.
Ancak amitripitilinin antidepresan aktivitesinde
adenozin ya da adenozin A2A reseptör antagonismasının
rolü olup olmadığına dair bilgi bulunmadığı için bu çalışmayı planladık.
Metod: Deneylerde antidepresan benzeri etkiyi tayin
için Balb-c fareler üzerinde zorunlu yüzme testi uygulanmıştır. Farelere serum fizyolojik (kontrol grubu),
amitriptilin, SCH 58261 (A2A reseptör antagonisti), SCH
58261+amitriptilin, adenozin, adenozin+amitriptilin
intraperitoneal yoldan uygulanmıştır.
Bulgular: Amitriptilin her iki dozunda da kontrol grubuna göre hareketsiz kalma zamanını azaltmıştır.
Amitriptilinin hareketsiz kalma süresini azaltıcı etkisi
SCH 58261 ile ön muamele edildiğinde daha da artmıştır. Adenozin ile amitriptilin birlikte uygulandığında ise
amitriptilinin hareketsiz kalma süresini azaltıcı etkisi
azalmakla birlikte bu etki istatistiksel olarak anlamlı
bulunmamıştır.
Tartışma: Amitriptilinin faredeki antidepresan benzeri
etkisinde adenozinerjik sistemin rolü olabileceği ve A2A
receptor antagonisti ile ön muamele edildiğinde bu
etkinin artabileceği gösterilmiştir. Bu bulgunun özellikle ilaca dirençli hastalarda önemli olabileceğini düşünmekteyiz.

Keywords

Amitriptilin, adenozin, adenozin A2A reseptör, antidepresan etki, fare

ADENOSINE A2A RECEPTOR ANTAGONISM INCREASED THE ANTIDEPRESSANT-LIKE EFFECT OF AMITRIPTYLINE IN MICE

Abstract

Objective: The role of the endogenous adenosinergic
system in the peripheral effect of an antidepressant
drug, amitriptyline, has been demonstrated in pain
models and also in cardiovascular toxicity induced by
amitriptyline. We performed this study as there is no
information on whether adenosine or adenosine A2A
receptor antagonists have any effect on the
antidepressant-like activity of amitriptyline in mice.
Methods: Balb-c mice were used in experiments and
forced swimming test was used to evaluate the
antidepressant-like activity. Mice were injected with
saline (control), amitriptyline, SCH 58261 (A2A receptor
antagonist), SCH 58261 + amitriptyline, adenosine,
adenosine + amitriptyline, intraperitoneally.
Results: Amitriptyline decreased immobility time
compared to control group at both doses. SCH 58261
did not produce antidepressant like effect in the applied
dose alone. Pretreatment of amitriptyline with SCH
58261 produced stronger inhibition of immobility time
than amitriptyline induced alone in the same dose. Coadministration of adenosine with amitriptyine,
however, it was not decreased the anti-immobility effect
of amitriptyline. However, it was not statistically
significant.
Conclusion: It has been demonstrated that
adenosinergic system may have a role in the
antidepressant-like activity of amitriptyline in mice, and
pretreatment with the A2A receptor antagonist may
induce a more pronounced antidepressant-like activity.
We are of the opinion that this finding may be of
particular importance in the case of drug resistant
patients. 

Keywords

Amitriptyline, adenosine, adenosine A2A receptor, antidepressan activity, mouse

References

• 1. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: From monoa mine s to gluta mate . Exp Clin Psychopharmacol 2015; 23:1–21. 2. W e s t e n b e r g H G M . P h a r m a c o l o g y o f antidepressants: Selectivity or Multiplicity? J Clin Psychiatry 1999; 60:S4-S8. 3. Stahl SM. Basic Psychopharmacology of Antidepressants, Part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 1998; 59:S5–S14. 4. Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard K. Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters. Chem Commun (Camb.) 2009; 25:3677-3692. 5. McCleane G. Antidepressants as analgesics. CNS Drugs 2008; 22:139-156. 6. Lawson K. A brief review of the pharmacology of amitriptyline and clinical outcomes in treating fibromyalgia. Biomedicines 2017; 5:1-12. 7. Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics: An overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 2001; 26:21-29. 8. Phillis JW, Wu PH. The effect of various centrally active drugs on adenosine uptake by the central nervous system Comp Biochem Physiol 1982; 72:179-187. 9. Phillis JW. Potentiation of the action of adenosine on cerebral cortical neurons by the tricyclic antidepressants. Br J Pharmacol 1984; 83:567–575. 10. Sawynok J, Reid AR, Liu XJ, Parkinson FE. Amitriptyline enhances extracellular tissue levels of adenosine in the rat hindpaw and inhibits adenosine uptake. Eur J Pharmacol 2005; 518:116- 122. 11. Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochimica et Biophysica Acta 2011; 1808:1380- 1399. 12. Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM. Adenosine and brain function. Int Rev Neurobiol 2005; 63:191-270. 13. Ribeiro JA, Sebastiao AM, Mendonca A. Adenosine r e c e p t o r s i n t h e n e r v o u s s y s t e m : pathophysiological implications. Prog Neurobiol 2003; 68:377-392. 14. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001; 24:31–55. 15. Cunha RA. Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade. Purinergic Signal 2005; 1:111-134. 16. Shen HY, Chen JF. Adenosine A2A Receptors in psychopharmacology: modulators of behavior, mood and cognition. Current Neuropharmacology 2009; 7:195-206. 17. Kulkarni SK, Mehta AK. Purino nucleoside-mediated immobility in mice: reversal by antidepressants Psychopharmacology 1985; 85:460-463. 18. Minor TR, Winslow L, Chang WC. Stress and Adenosine: II. Adenosine analogs mimic the effect of inescapable shock on shuttle-escape performance in rats. Behav Neurosci 1994; 108:265-276. 19. El Yacoubi M, Ledent C, Parmentier M, et al. Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice. Br J Pharmacol 2001; 134:68-77. 20. El Yacoubi M, Costentin J, Vaugeois JM. Adenosine A2A receptors and depression. Neurology 2003; 61:S82–S87. 21. Hodgson RA, Bertorelli R, Varty GB, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl] ethyl]-2-(2-furanyl)-7hpyrazolo[4,3-e][1,2,4] triazolo[1,5-c] pyrimidin-5-amine in rodent models of movement disorders and depression. J Pharmacol Exp Ther 2009; 330:294-303. 22. Yamada K, Kobayashi M, Mori A, Jenner P, Kanda T. Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents. Pharmacol Biochem Behav 2013; 114- 115:23-30. 23. Yamada K, Kobayashi M, Shiozaki S, et al. Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. Psychopharmacology 2014; 231:2839–2849. 24. Minor TR, Hanff TC. Adenosine signaling in reserpine-induced depression in rats. Behav Brain Res 2015; 286:184-191. 25. Kaster MP, Machado NJ, Silva HB, et al. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci 2015; 112:7833-7838. 26. Kaster MP, Rosa AO, Rosso MM, et al. Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci Lett 2004; 355:21-24. 27. Kaster MP, Santos AR, Rodrigues AL. Involvement of 5-HT1A receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test. Brain Res Bull 2005; 67:53-61. 28. Kaster MP, Budni J, Gazal M, et al. The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A2A receptors. Purinergic Signal 2013; 9:481–486. 29. Deckert J, Gleiter CH. Adenosinergic psychopharmaceuticals? Trends Pharmacol Sci 1989; 10:99-100. 30. Kalkan S, Hocaoglu N, Buyukdeligoz M, Gurdal H. Binding of amitriptyline to adenosine A1or A2aReceptors using radioligand binding assay. International Journal of Pharmacolology 2018; 14:116-120. 31. Barcellos CK, Schetinger MR, Dias RD, Sarkis JJ. In vitro effect of central nervous system active drugs on the ATP a se -AD Pa se a ctivity a nd acetylcholinesterase activity from cerebral cortex of adult rats. Gen Pharmacol 1998; 31:563-567. 32. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229:327–336. 33. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996; 29:2-11. 34. Liu J, Reid AR, Sawynok J. Spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline. Eur J Pharmacol 2013; 698:213–219. 35. Ulugol A, Karadag HC, Tamer M, et al. Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci Lett 2002; 328:129-132. 36. Kalkan S, Aygoren O, Akgun A, et al. Do adenosine receptors play a role in amitriptyline induced cardiovascular toxicity in rats. J Toxicol Clin Toxicol 2004; 42:945–954. 37. Kalkan S, Hocaoglu N, Oransay K, Buyukdeligoz M, Tuncok Y. Adenosine-mediated cardiovascular toxicity in amitriptyline-poisoned rats. Drug Chem Toxicol 2012; 35:423-431. 38. Zahorodna A, Bijak M, Hess G. Differential effects of repeated imipramine on hippocampal responsiveness to adenosine and serotonin. Eur Neuropsychopharmacol 2002; 12:355–360. 39. Kuzmin A, Johansson B, Gimenez L, Ogren SO, Fredholm BB. Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimula tion in mice . Eur Neuropsychopharmacol 2006; 16:129-136.40. Crema LM, Pettenuzzo LF, Schlabitz M, et al. The effect of unpredictable chronic mild stress on depressive-like behavior and on hippocampal A1 and striatal A2A adenosine receptors. Physiol Behav 2013; 109:1-7. 41. Berk M, Plein H, Ferreira D, Jersky B. Blunted adenosine A2A receptor function in platelets in patients with major depression. Eur Neuropsychopharmacol. 2001; 11:183-186. 42. Okada M, Nutt DJ, Murakami T, et al. Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release. J Neurosci 2001; 21:628–640. 43. Yamato T, Yamasaki S, Misumi Y, et al. Modulation of the stress response by coffee: an in vivo microdialysis study of hippocampal serotonin and dopamine levels in rat. Neurosci Lett 2002; 332:87- 90. 44. Fuxe K, Ferré S, Genedani S, Franco R, Agnati LF. Adenosine receptor -dopamine receptor interactions in the basal ganglia and their relevance for brain function. Physiol Behav 2007; 92:210– 217.