Mahluga JAFAROVA DEMİRKAPU, Furkan Cuma DOĞAN, Sevil KARABAG, Ahsen YİLMAZ, Aliye ÇELİKKOL, Hasan Raci YANANLI

Akut topiramat uygulamasının sıçanlardaki travma sonrası stres bozukluğu üzerine etkileri

Amaç: Bu çalışmada, travma sonrası stres bozukluğu sıçan modelinde akut sistemik topiramat uygulamasının anksiyete indeksi ve donakalma zamanı, plazma östrojen ve progesteron düzeyleri ile tükürük bezi immünoglobulin A üzerine etkilerinin araştırılması amaçlanmıştırı. Gereç ve Yöntem: Çalışmada kullanılan toplam on sekiz dişi Wistar sıçan yırtıcı koku stresine maruz bırakıldı. Bir hafta sonra kontrol grubuna serum fizyolojik, tedavi gruplarına 15 µM ve 30 µM topiramat uygulandı, ardından hayvanlar travma hatırlatıcısına maruz bırakıldı ve davranışları yükseltilmiş artı labirentinde izlendi. Deneyin sonunda kan örnekleri alındı, sakrifiye edilen hayvanların tükürük bezleri çıkarıldı. Bulgular: Topiramat travma sonrası stres bozukluğu olan sıçanlarda hem 15 µM hem de 30 µM dozlarda kontrol grubuna kıyasla kaygı indeksini ve donakalma zamanını baskıladı. Kontrol grubunda plazma östrojen düzeyi ile kaygı indeksi arasında pozitif korelasyon gözlendi, topiramat bu korelasyonu doza bağımlı olarak baskıladı. Topiramat plazma progesteron seviyesini değiştirmedi, fakat tükürük bezi immünoglobulin A seviyesini düşük dozda baskıladı. Sonuç: Çalışmamızda elde edilen bu bulgular topiramatın travma sonrası stres bozukluğu tedavisinde etkili olabileceğine işaret etmektedir.

Anahtar Kelimeler:

Kaygı indeksi, östrojen, donakalma zamanı, progesteron, tükürük immünoglobulin A

Effects of acute topiramate administration on post-traumatic stress disorder in rats

Purpose: The aim of this study was to investigate the effects of acute systemic topiramate administration on anxiety index and freezing time, plasma estrogen and progesterone levels, and salivary gland immunoglobulin A in a post-traumatic stress disorder rat model. Materials and Methods: A total of eighteen female Wistar rats used in the study were exposed to predatory odor stress. One week later, saline was administered to the control group and 15 µM and 30 µM topiramate to the treatment groups, after which the animals were exposed to the trauma reminder and their behavior was monitored in the elevated plus maze. At the end of the experiment, blood samples were taken, animals were sacrificed, salivary glands were removed immediately after. Results: Topiramate suppressed anxiety index and freezing time in rats with post-traumatic stress disorder at both 15 µM and 30 µM doses compared to the control group. A positive correlation was observed between plasma estrogen level and anxiety index in the control group, and topiramate suppressed this correlation in a dose-dependent manner. Topiramate did not change the plasma progesterone level, but suppressed the salivary gland immunoglobulin A level at the low dose. Conclusion: These findings obtained in our study indicate that topiramate may be effective in the treatment of post-traumatic stress disorder.

Keywords:

Anxiety index, estrogen, freezing time, progesterone, salivary immunoglobulin A,

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1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington DC, American Psychiatric Association. 2013.
2. Nuss P. Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis Treat. 2015;11:165-75.
3. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012;13:769-87.
4. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259-84.
5. Macpherson AJ, Geuking MB, McCoy KD. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology. 2005;115:153-62.
6. Ulmer-Yaniv A, Djalovski A, Yirmiya K, Halevi G, Zagoory-Sharon O, Feldman R. Maternal immune and affiliative biomarkers and sensitive parenting mediate the effects of chronic early trauma on child anxiety. Psychol Med. 2018;48:1020-33.
7. Yirmiya K, Djalovski A, Motsan S, Zagoory-Sharon O, Feldman R. Stress and immune biomarkers interact with parenting behavior to shape anxiety symptoms in trauma-exposed youth. Psychoneuroendocrinology. 2018;98:153-60.
8. Coventry PA, Meader N, Melton H, Temple M, Dale H, Wright K et al. Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: Systematic review and component network meta-analysis. PLoS Med. 2020;17:e1003262.
9. Maryanoff BE. Sugar sulfamates for seizure control: discovery and development of topiramate, a structurally unique antiepileptic drug. Curr Top Med Chem. 2009;9:1049-62.
10. Özkula S, Dundar OH, Erol S, Bakar R, Gecit H, Turan NE et al. The effects of topiramate applied to the nucleus accumbens region on morphine withdrawal syndrome. NKMJ. 2020;8:240-8.
11. Mula M, Cavanna AE, Monaco F. Psychopharmacology of topiramate: from epilepsy to bipolar disorder. Neuropsychiatr Dis Treat. 2006;2:475-88.
12. Berlant JL. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry. 2004;4:24.
13. Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002;63:15-20.
14. Hoskins MD, Bridges J, Sinnerton R, Nakamura A, Underwood JFG, Slater A et al. Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. Eur J Psychotraumatol. 2021;12:1802920.
15. de Moraes Costa G, Zanatta FB, Ziegelmann PK, Soares Barros AJ, Mello CF. Pharmacological treatments for adults with post-traumatic stress disorder: A network meta-analysis of comparative efficacy and acceptability. J Psychiatr Res. 2020;130:412-20.
16. Zullino DF, Krenz S, Besson J. AMPA blockade may be the mechanism underlying the efficacy of topiramate in PTSD. J Clin Psychiatry. 2003;64:219- 20.
17. Adamec RE, Shallow T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol Behav. 1993;54:101-9.
18. Tanriverdi AM, Aydin B, Bebitoglu BT, Cabadak H, Goren MZ. The behavioral and neurochemical effects of methylprednisolone or metyrapone in a posttraumatic stress disorder rat model. North Clin Istanb. 2019;6:327-33.
19. Davis M. Neural circuitry of anxiety and stress disorders. In: Neuropsychopharmacology: The Fifth Generation of Progress (Eds Davis KL, Charney D, Coyle JT, Nemeroff C):729-43.Philadelphia, Lippincott, Williams, Wilkins; 2002.
20. Royer S, Martina M, Paré D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J Neurosci. 1999;19:10575- 83.
21. Jongen-Rêlo AL, Amaral DG. Evidence for a GABAergic projection from the central nucleus of the amygdala to the brainstem of the macaque monkey: a combined retrograde tracing and in situ hybridization study. Eur J Neurosci. 1998;10:2924-33.
22. Etkin A. Functional neuroanatomy of anxiety: a neural circuit perspective. Curr Top Behav Neurosci. 2010;2:251-77.
23. Kober H, Barrett LF, Joseph J, Bliss-Moreau E, Lindquist K, Wager TD. Functional grouping and cortical-subcortical interactions in emotion: a metaanalysis of neuroimaging studies. Neuroimage. 2008;42:998-1031.
24. Sanders SK, Shekhar A. Regulation of anxiety by GABAA receptors in the rat amygdala. Pharmacol Biochem Behav. 1995;52:701-6.
25. Solati J, Hajikhani R, Golub Y. Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response. Acta Neuropsychiatr. 2013;25:221-6.
26. Barbalho CA, Nunes-de-Souza RL, Canto-de-Souza A. Similar anxiolytic-like effects following intraamygdala infusions of benzodiazepine receptor agonist and antagonist: evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus-maze test. Brain Res. 2009;1267:65-76.
27. Heldt SA, Mou L, Ressler KJ. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Transl Psychiatry. 2012;2:e181.
28. Dunn RW, Corbett R, Fielding S. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur J Pharmacol. 1989;169:1-10.
29. Karcz-Kubicha M, Liljequist S. Evidence for an anxiogenic action of AMPA receptor antagonists in the plus-maze test. Eur J Pharmacol. 1995;279:171-7.
30. Kotlinska J, Liljequist S. The putative AMPA receptor antagonist, LY326325, produces anxiolytic-like effects without altering locomotor activity in rats. Pharmacol Biochem Behav. 1998;60:119-24.
31. Pati S, Sood A, Mukhopadhyay S, Vaidya VA. Acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour. J Biosci. 2018;43:85-95.
32. Maren S, Holt WG. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus. Behav Neurosci. 2004;118:97- 110.
33. Fani N, Tone EB, Phifer J, Norrholm SD, Bradley B, Ressler KJ et al. Attention bias toward threat is associated with exaggerated fear expression and impaired extinction in PTSD. Psychol Med. 2012;42:533-43.
34. Siegmund A, Wotjak CT. A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. J Psychiatr Res. 2007;41:848-60.
35. Zhang LM, Yao JZ, Li Y, Li K, Chen HX, Zhang YZ et al. Anxiolytic effects of flavonoids in animal models of posttraumatic stress disorder. Evid Based Complement Alternat Med. 2012;2012:623753.
36. Carey MP, Deterd CH, de Koning J, Helmerhorst F, de Kloet ER. The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. J Endocrinol. 1995;144:311-21.
37. Ter Horst GJ, Wichmann R, Gerrits M, Westenbroek C, Lin Y. Sex differences in stress responses: focus on ovarian hormones. Physiol Behav. 2009;97:239-49.
38. Lebron-Milad K, Milad MR. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol Mood Anxiety Disord. 2012;2:3.
39. Marcondes FK, Miguel KJ, Melo LL, SpadariBratfisch RC. Estrous cycle influences the response of female rats in the elevated plus-maze test. Physiol Behav. 2001;74:435-40.
40. Shors TJ, Leuner B. Estrogen-mediated effects on depression and memory formation in females. J Affect Disord. 2003;74:85-96.
41. Pineles SL, Nillni YI, Pinna G, Irvine J, Webb A, Arditte Hall KA et al. PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in plasma. Psychoneuroendocrinology. 2018;93:133-41.
42. Reynolds TA, Makhanova A, Marcinkowska UM, Jasienska G, McNulty JK, Eckel LA et al. Progesterone and women's anxiety across the menstrual cycle. Horm Behav. 2018;102:34-40.
43. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol. 1995;7:171-7.
44. Phillips AC, Carroll D, Evans P, Bosch JA, Clow A, Hucklebridge F et al. Stressful life events are associated with low secretion rates of immunoglobulin A in saliva in the middle aged and elderly. Brain Behav Immun. 2006;20:191-7.
45. Fan Y, Tang Y, Lu Q, Feng S, Yu Q, Sui D et al. Dynamic changes in salivary cortisol and secretory immunoglobulin A response to acute stress. Stress and Health. 2009;25:189–94.
46. Volkmann ER, Weekes NY. Basal SIgA and cortisol levels predict stress-related health outcomes. Stress and Health. 2006;22:11–23.