The present study was designed to investigate the effectiveness of trihexyphenidyl, a central anticholinergic drug, in preventing the post-traumatic stress disorder (PTSD) symptoms in a mouse model.
Mice were subjected to underwater trauma stress for 30 s on day 1 followed by three situational reminders (3rd, 7th and 14th day). Thereafter, the behavioral alterations including freezing behavior were noted on 21st day. The serum corticosterone levels were measured as a biochemical marker of trauma. Elevated plus maze test was done on day 1 and day 2 to assess the memory formation following exposure to trauma.
Trauma and situational reminders were associated with a significant development of behavioral changes and freezing behavior on the 21st day. Moreover, there was also a significant decrease in the serum corticosterone levels. A single administration of trihexyphenidyl (2 and 5 mg/kg) significantly restored trauma associated-behavioral changes and serum corticosterone levels. Moreover, it significantly increased the transfer latency time on day 2 following stress exposure in comparison to normal mice suggesting the inhibition of memory formation during trauma exposure. Trihexyphenidyl also led to significant reduction in freezing behavior in response to situational reminders again suggesting the inhibition of formation of aversive fear memory.
The blockade of central muscarinic receptors may block the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders. Central anticholinergic agents may be potentially useful as prophylactic agents in preventing the development of PTSD symptoms.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Ethical approval: The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) (Reg. no. 1407/PO/Re/S/11CPCSEA) and care of the animal’s experiment was carried out as per the guidelines of the Committee for the Purpose of Control and Supervision of Experimental Animals (CPCSEA), Ministry of Environment and Forests, Government of India (approval no. ATRC/ 02/18).
Informed consent: Informed consent was obtained from all individuals included in this study.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed. Washington DC: 2013. Search in Google Scholar
2. Chen, C, Ji, M, Xu, Q, Zhang, Y, Sun, Q, Liu, J, et al. Sevoflurane attenuates stress-enhanced fear learning by regulating hippocampal BDNF expression and Akt/GSK-3β signaling pathway in a rat model of post-traumatic stress disorder. J Anesth 2015;29:600–8. http://doi.org/10.1007/s00540-014-1964-x. Search in Google Scholar
3. Foa, EB. Psychosocial treatment of post-traumatic stress disorder. J Clin Psychiatry 2000;61:43–8. PMID:10761678. Search in Google Scholar
4. Koek, RJ, Langevin, JP, Krahl, SE, Kosoyan, HJ, Schwartz, HN, Chen, JW, et al. Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation. Trials 2014;15:356. http://doi.org/10.1186/1745-6215-15-356. Search in Google Scholar
5. Schelling, G, Briegel, J, Roozendaal, B, Stoll, C, Rothenhäusler, HB, Kapfhammer, HP. The effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder in survivors. Biol Psychiatry 2001;50:978–85. http://doi.org/10.1016/s0006-3223(01)01270-7. Search in Google Scholar
6. Bustos, SG, Giachero, M, Maldonado, H, Molina, VA. Previous stress attenuates the susceptibility to Midazolam’s disruptive effect on fear memory reconsolidation: influence of pre-reactivation D-cycloserine administration. Neuropsychopharmacology 2010;35:1097–108. http://doi.org/10.1038/npp.2009.215. Search in Google Scholar
7. Holbrook, TL, Galarneau, MR, Dye, JL, Quinn, K, Dougherty, AL. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med 2010;362:110–17. http://doi.org/10.1056/nejmoa0903326. Search in Google Scholar
8. Bandelow, B, Sher, L, Bunevicius, R, Hollander, E, Kasper, S, Zohar, J, et al. OCD and PTSD guidelines for the pharmacological treatment of anxiety disorders, obsessive compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract 2012;16:77–84. http://doi.org/10.3109/13651501.2012.667114. Search in Google Scholar
9. Steckler, T, Risbrough, V. Pharmacological treatment of PTSD established and new approaches. Neuropharmacology 2012;62:617–27. http://doi.org/10.1016/j.neuropharm.2011.06.012. Search in Google Scholar
10. Hruska, B, Cullen, PK, Delahanty, DL. Pharmacological modulation of acute trauma memories to prevent PTSD: considerations from a developmental perspective. Neurobiol Learn Mem 2014;112:122–9. http://doi.org/10.1016/j.nlm.2014.02.001. Search in Google Scholar
11. Roque, AP. Pharmacotherapy as prophylactic treatment of post-traumatic stress disorder: a review of the literature. Issues Ment Health Nurs 2015;36:740–51. http://doi.org/10.3109/01612840.2015.1057785. Search in Google Scholar
12. Rafiq, S, Ahmad, S, Ahmed, F, Batool, Z, Ahmed, SB, Saleem, S, et al. Anticholinergic drug atropine diminishes newly formed fear memory in male rats. Pak J Pharma Sci 2018;31:1075–9. PMID: 29731446. Search in Google Scholar
14. Feiro, O, Gould, TJ. The interactive effects of nicotinic and muscarinic cholinergic receptor inhibition on fear conditioning in young and aged C57BL/6 mice. Pharmacol Biochem Behav 2005;80:251–62. http://doi.org/10.1016/j.pbb.2004.11.005. Search in Google Scholar
16. Javadi-Paydar, M, Rayatnia, F, Fakhraei, N, Zakeri, M, Mirazi, N, Norouzi, A, et al. Atorvastatin improved scopolamine-induced impairment in memory acquisition in mice: involvement of nitric oxide. Brain Res 2011;1386:89–99. http://doi.org/10.1016/j.brainres.2011.02.057. Search in Google Scholar
17. Bucherelli, C, Baldi, E, Mariottini, C, Passani, MB, Blandina, P. Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation. Learn Memory 2006;13:426–30. http://doi.org/10.1101/lm.326906. Search in Google Scholar
18. Vazdarjanova, A, McGaugh, JL. Basolateral amygdala is involved in modulating consolidation of memory for classical fear conditioning. J Neurosci 1999;19:6615–22. http://doi.org/10.1523/jneurosci.19-15-06615.1999. Search in Google Scholar
19. Young, MB, Thomas, SA. M1-muscarinic receptors promote fear memory consolidation via phospholipase C and the M-current. J Neuroscience 2014;34:1570–8. http://doi.org/10.1523/jneurosci.1040-13.2014. Search in Google Scholar
20. Patricio, RR, Soares, JCK, Oliveria, MGM. M1 muscarinic receptors are necessary for retrieval of remote context fear memory. Phsyiol Behav 2017;169:202–7. http://doi.org/10.1016/j.physbeh.2016.12.008. Search in Google Scholar
21. Baba, Y, Higuchi, MA, Abe, H, Fukuyama, K, Onozawa, R, Uehara, Y, et al. Anti-cholinergics for axial symptoms in Parkinson’s disease after subthalamic stimulation. Clin Neurol Neurosurg 2012;114:1308–11. http://doi.org/10.1016/j.clineuro.2012.03.046. Search in Google Scholar
22. Saito, T, Katayama, T, Sawada, J, Kano, K, Asanome, A, Takahashi, K, et al. Combination therapy for segmental craniocervical dystonia (Meige syndrome) with aripiprazole, trihexyphenidyl, and botulinum toxin: three cases reports. Neurol Sci 2015;36:243–5. http://doi.org/10.1007/s10072-014-1927-x. Search in Google Scholar
23. Spivak, B, Adlersberg, S, Rosen, L, Gonen, N, Mester, R, Weizman, A. Trihexyphenidyl treatment of clozapine-induced hypersalivation. Int Clin Psychopharmacol 1997;12:213–5. http://doi.org/10.1097/00004850-199707000-00005. Search in Google Scholar
24. Nakra, BR, Margolis, RB, Gfeller, JD, Grossberg, GT, Sata, LS. The effect of a single low dose of trihexyphenidyl on memory functioning in the healthy elderly. Int Psychogeriatr 1992;4:207–14. http://doi.org/10.1017/s1041610292001030. Search in Google Scholar
25. Miao, YL, Guo, WZ, Shi, WZ, Fang, WW, Liu, Y, Liu, J, et al. Midazolam ameliorates the behavior deficits of a rat post-traumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PLoS One 2014;9: e101450. http://doi.org/10.1371/journal.pone.0101450. Search in Google Scholar
26. Shimizu, S, Mizuguchi, Y, Sobue, A, Fujiwara, M, Morimoto, T, Ohno, Y. Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice. J Pharm Sci 2015;127:439–45. http://doi.org/10.1016/j.jphs.2015.03.004. Search in Google Scholar
27. Lapiz-Bluhm, MD, Bondi, CO, Doyen, J, Rodriguez, GA, Bédard-Arana, T, Morilak, DA. Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats. J Neuroendocrinol 2008;20:1115–37. http://doi.org/10.1111/j.1365-2826.2008.01772.x. Search in Google Scholar
28. Chauhan, E, Bali, A, Singh, N, Jaggi, AS. Pharmacological investigations on cross adaptation in mice subjected to stress immobilization. Life Sci 2015;127:98–105. Search in Google Scholar
29. Ritov, G, Ardi, Z, Richter-Levin, G. Differential activation of amygdala, dorsal and ventral hippocampus following an exposure to a reminder of underwater trauma. Front Behav Neurosci 2014;8:18. https://doi.org/10.3389/fnbeh.2014.00018. Search in Google Scholar
30. Ardi, Z, Ritov, G, Lucas, M, Richter-Levin, G. The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus. Int J Neuropsychopharmacol 2014;17:571–80. http://doi.org/10.1017/s1461145713001272. Search in Google Scholar
31. Bhatia, N, Jaggi, AS, Singh, N, Anand, P, Dhawan, R. Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis. J Nat Med 2011;65:532–43. http://doi.org/10.1007/s11418-011-0535-9. Search in Google Scholar
32. Mair, SF. Exposure to the stressor environment prevents the temporal dissipation of behavioral depression/learned helplessness. Biol Psychiatry 2001;49:763–73. https://10.1016/s0006-3223(00)01095-7. Search in Google Scholar
33. Siegmund, A, Wotjak, CT. A mouse model of post-traumatic stress disorder that distinguishes between conditioned and sensitized fear. J Psychiatr Res 2007;41:848–60. http://doi.org/10.1016/j.jpsychires.2006.07.017. Search in Google Scholar
34. Zhang, LM, Yao, JZ, Li, Y, Chen, HX, Zhang, YZ, Li, YF. Anxiolytic effects of flavonoids in animal models of post-traumatic stress disorder. Evid Based Complement Alternat Med 2012;2012:623753. http://doi.org/10.1155/2012/623753. Search in Google Scholar
35. Li, XM, Su, F, Ji, MH, Zhang, GF, Qiu, LL, Jia, M, et al. Disruption of hippocampal neuregulin 1-ErbB4 signaling contributes to the hippocampus-dependent cognitive impairment induced by isoflurane in aged mice. Anesthesiology 2014;121:79–88. http://doi.org/10.1097/aln.0000000000000191. Search in Google Scholar
36. Terhorst, D, Blume-Peytavi, U, Schönian, G, Schewe, C, Haas, N, Burbach, GJ. Leishmaniasis: a reminder in the face of forgotten travel. J Pediatr 2012;161:966. http://doi.org/10.1016/j.jpeds.2012.05.013. Search in Google Scholar
37. Verma, M, Bali, A, Singh, N, Jaggi, AS. Investigating the role of nisoldipine in foot-shock-induced post-traumatic stress disorder in mice. Fundam Clin Pharmacol 2016;30:128–36. http://doi.org/10.1111/fcp.12174. Search in Google Scholar
38. Kaur, R, Jaggi, AS, Singh, N. Studies on effect of stress preconditioning in restrain stress-induced behavioral alterations. Yakugaku Zasshi 2010;130:215–21. http://doi.org/10.1248/yakushi.130.215. Search in Google Scholar
39. Agrawal, A, Jaggi, AS, Singh, N. Pharmacological investigations on adaptation in rats subjected to cold water immersion stress. Physiol Behav 2011;103:321–9. http://doi.org/10.1016/j.physbeh.2011.02.014. Search in Google Scholar
40. Ji, LL, Tong, L, Xu, BK, Fu, CH, Shu, W, Peng, JB, et al. Intra-hippocampal administration of ZIP alleviates. Behav Brain Funct 2014;10:28. http://doi.org/10.1186/1744-9081-10-28. Search in Google Scholar
42. Richter-Levin, G. Acute and long term behavioral correlates of underwater trauma-potential relevance to stress and post-stress syndromes. Psychiatry Res 1998;79:73–83. http://doi.org/10.1016/s0165-1781(98)00030-4. Search in Google Scholar
43. Moore, NL, Gauchan, S, Genovese, RF. Differential severity of anxiogenic effects resulting from a brief swim or underwater trauma in adolescent male rats. Pharmacol Biochem Behav 2012;102:264–8. http://doi.org/10.1016/j.pbb.2012.05.002. Search in Google Scholar
44. Knox, D, George, SA, Fitzpatrick, CJ, Rabinak, CA, Maren, S, Liberzon, I. Single prolonged stress disrupts retention of extinguished fear in rats. Learn Mem 2012;19:43–9. http://doi.org/10.1101/lm.024356.111. Search in Google Scholar
45. Zoladz, PR, Fleshner, M, Diamond, DM. Psychosocial animal model of PTSD produces a long-lasting traumatic memory, an increase in general anxiety and PTSD-like glucocorticoid abnormalities. Psychoneuroendocrinology 2012;37:1531–45. http://doi.org/10.1016/j.psyneuen.2012.02.007. Search in Google Scholar
46. Aslan, N, Goren, Z, Onat, F, Oktay, S. Carbachol-induced pressor responses and muscarinic M1 receptors in the central nucleus of amygdala in conscious rats. Eur J Pharmacol 1997;333:63–7. http://doi.org/10.1016/s0014-2999(97)01106-0. Search in Google Scholar
47. Ravindran, LN, Stein, MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry 2010;71:839–54. http://doi.org/10.4088/jcp.10r06218blu. Search in Google Scholar
48. McLay, RN, Ho, J. Post-traumatic stress disorder-like symptoms after treatment with acetylcholinesterase inhibitors. J Neuropsychiatry Clin Neurosci 2007;19:92–3. http://doi.org/10.1176/jnp.2007.19.1.92. Search in Google Scholar
49. Sogo, K. Trihexyphenidyl reduces flashbacks in patients with posttraumatic stress disorder (PTSD). Case Report. J Trauma Stress Disor Treat 2015;4:1. 10.4172./2324-8947.1000140. Search in Google Scholar
50. Terzioğlu, B, Kaleli, M, Aydın, B, Ketenci, S, Cabadak, H, Gören, MZ. Increased noradrenaline levels in the rostral pons can be reversed by M1 antagonist in a rat model of post-traumatic stress disorder. Behav Neurosci 2016;130:29–35. Search in Google Scholar
51. Yehuda, R, Yang, RK, Golier, JA, Grossman, RA, Bierer, LM, Tischler, L. Effect of sertraline on glucocorticoid sensitivity of mononuclear leukocytes in post-traumatic stress disorder. Neuropsycopharmacology 2006;31:189–96. http://doi.org/10.1038/sj.npp.1300862. Search in Google Scholar
52. Imperato, A, Puglisi-Allegra, S, Casolini, P, Angellucci, L. Changes in brain dopamine and acetylcholine release during and following stress are independent of the pituitary-adrenocortical axis. Brain Res 1991;538:111–7. http://doi.org/10.1016/0006-8993(91)90384-8. Search in Google Scholar
53. Ennis, M, Shipley, MT. Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: increased discharge rate and induction of c-fos. Exp Neurol 1992;118:164–77. http://doi.org/10.1016/0014-4886(92)90033-m. Search in Google Scholar
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