Sıçan farklı beyin bölgelerinde M1 muskarinik reseptör alt tipi seviyeleri

Amaç: Travma sonrası stres bozukluğu (TSSB) yaşamı tehdit edentravma, aşırı uyarılma, flashbackler ve kabuslar ile karakterizedir.TSSB araştırmaları, travmatik bir deneyimin beyinin davranışve işlevleri üzerinde uzun süreli bozulma etkilerine yol açtığınıanlamanın zorluğuyla karşı karşıyadır. Herhangi bir spesifik ajanınetkinliğini destekleyecek uygun kanıt olmadığında, TSSB’ninfarmakoterapisinde birçok farmakolojik ajan kullanılmaktadır.Olumsuz bir deneyimin geri çağrılmasında M1 muskarinik reseptöralt tiplerinin önemli rol oynayabileceği öngörülmektedir. Buaraştırmanın amacı, TSSB’de kronik fluoksetin (FLU) (2.5 mg/gün; i.p) tedavisinin hem davranışsal hem de moleküler etkinliğinive farmakoterapinin sıçanlarda M1 muskarinik reseptör alt tipiekspresyonu üzerine muhtemel etkisini araştırmaktır.Gereç ve Yöntem: Deney tasarımında tüm gruplar rastgeleolarak seçilerek Kontrol, Stres ve Tedavi grupları oluşturulmuştur.Kronik FLU tedavisinin etkileri, sıçan hipokampüs ve frontalkorteksinde, M1 reseptörlerinin ekspresyon seviyeleri açısındandeğerlendirilmiştir.Bulgular: Sıçanlar deneyin son gününde (30.Gün) travmahatırlatıcılara maruz kaldıklarında, stres gruplarındaki anksiyeteindekslerinin kontrol grubuna göre belirgin bir şekilde arttığıgözlemlenmiştir (P<0.001). Ayrıca, kronik FLU tedavisinin stressgruplarında anksiyete değerlerini düşürerek geriye döndürdüğügözlemlenmiştir (P<0.001).Sonuç: Bu çalışmada, stresin kaygı benzeri davranışlarıarttırarak sıçan beyin hipokampüs ve frontal korteksinde M1ekspresyon seviyesini azalttığı gözlemlenmiştir. Düşük dozkronik FLU tedavisi ile bu etkilerin geri döndürülebileceğiöngörülmektedir.

Anahtar Kelimeler:

Muskarinik reseptör, Stres, Kedi kumu, Fluoksetin, Hippokampüs, Frontal korteks

The expression level of muscarinic M1 receptor subtypes in different regions of rat brain

Objectives: Post-traumatic stress disorder (PTSD) is characterizedby life threatening trauma, overexcitation, flashbacks andnightmares. Research on PTSD is faced with the challenge ofunderstanding how a traumatic experience leads to long lastingdetrimental effects on behavior and functions of the brain. Manypharmacological agents are available in the pharmacotherapyof the PTSD where there is no adequate evidence to support theefficacy of any specific agent. It is hypothesized that M1 muscarinicreceptor subtypes might play important role in the recall ofnegative experience. The aim of this research is to investigate boththe behavioral and the molecular efficacy of chronic fluoxetine(FLU) (2.5mg/day; i.p) treatment in PTSD and also the probableeffect of pharmacotherapy on M1 muscarinic receptor subtypeexpression in rats.Materials and Methods: For experimental design randomselection was performed to all groups; Control, Stress andTreatment groups. The effects of chronic FLU treatment wereevaluated in terms of expression levels of the M1 receptors in thehippocampus and the frontal cortex of the rats’ brain.Results: When the rats were subjected to the trauma reminderon the last day of the experiment (Day 30), the anxiety indexesof the stress group were found to be significantly higher than thecontrol (P< 0.001). Moreover, it has been observed that chronicFLU treatment restored the anxiety scores in stress groups bylowering the anxiety indexes (P< 0.001).Conclusion: In this study, it has been indicated that stressinduces anxiety like behavior and reduces M1 expression in thehippocampus and the frontal cortex of the rats’ brain. These effectscan be prevented by lowering the dose of chronic FLU therapy.

Keywords:

Muscarinic receptors, Stress, Cat litter, Fluoxetine, Hippocampus, Frontal cortex,

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Schmidt U, Kaltwasser SF, Wotjak CT. Biomarkers in posttraumatic stress disorder: overview and ımplications for future research. Dis Markers 2013;1:43-54. doi:10.1155/2013/835876
Yehuda R. Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry 2004;65:26-36.
Vanelzakker MB, Dahlgren MK, Davis FC, et al. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiol Learn Mem 2014;113:3-18. doi: 10.1016/j.nlm.2013.11.014.
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. Eu J Pharmacol 1997;333:63-7.
Ravindran LN, Stein MB. Pharmacotherapy of PTSD: premises, principles, and priorities. Brain Res Rev 2009;1293:24-39. doi: 10.1016/j.brainres.2009.03.037.
Armario A, Escorihuela RM, Nadal R. Long-term neuroendocrine and behavioral effects of a single exposure to stress in adult animals. Neurosci Biobehav Rev 2008;32:1121-35. doi: 10.1016/j.neubiorev.2008.04.003
Cohen H, Zohar J, Matar MA. The relevance of differential response to traumain an animal model of posttraumatic stress disorder. Biol Psychiatry 2003;59:1208-18. doi:10.1016/j. ejphar.2004.09.009
Adamec R, Bartoszyk GD, Burton P. Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats. Eu J Pharmacol 2004;504:65-77.
Kafkafi N, Lipkind D, Benjamini Y, Golani I. SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions. Behav Neurosci 2003;117:464-77. doi: 10.1517/14728210902972494
Baker DG, Nievergelt CM, Risbrough VB. Posttraumatic stress disorder: emerging concepts of pharmacotherapy. Expert Opin Emerg Drugs 2009;14:251-72. doi: 10.1517/14728210902972494.
Mendes DD, Mello MF, Ventura P, Passarela CM, Mari JJ. A systematic review on the effectiveness of cognitive behavioral therapy for posttraumatic stress disorder. Int J Psychiatry Med 2008;38:241-59. doi: 10.2190/PM.38.3.b
Cohen H, Matar MA, Richter-Levin G, Zohar J. The contribution of an animal model toward uncovering biological risk factors for PTSD. Ann N Y Acad Sci 2006;1071:335-50. doi: 10.1196/annals.1364.026
Matar MA, Cohen H, Kaplan Z, Zohar J. The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 2006;31:2610-8. doi : 10.1038/sj.npp.1301132
Mazor A, Matar MA, Kaplan Z, Koziovsky N, Zohar J, Cohen H. Gender related qualitative differences in baseline and post-stress anxiety responses are not reflected in the incidence of criterion-based PTSD-like behaviour patterns. World J Biol Psychiatry. 2009;10:856–69. PMID:2864480
Blancharda DC, Griebelc G, Blanchardd RJ. Conditioning and residual emotionality effects of predator stimuli: some reflections on stress and emotion. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27:1177–85. doi:10.1016/j.pnpbp.2003.09.012
Pelow S, Chopin P, File SE, Briley M. Validation of openclosed arm entries in an elevated plus maze as measure of anxiety in the rat. J Neurosci Methods. 1985;14:149–67. PMID:2864480
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2nd ed. London: Academic Press; 1986.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–327. PMID:14907713
Zoladz PR, Diamond DM. Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis. Exp Neurol. 2016; 284:211–9. doi: 10.1016/j.expneurol.2016.06.003
Wall PM, Flinn J, Messier C. Infralimbic muscarinic M1 receptors modulate anxiety-like behavior and spontaneous working memory in mice. Psychopharmacology 2004;155:58–68. PMID: 11374337
Degroot A, Nomikos GG. Fluoxetine disrupts the integration between anxiety and aversive memories. Neuropsychopharmacology 2005;30:391–400. doi:10.1038/ sj.npp.1300624
Cohen H, Liu T , Kozlovsky N, Kaplan Z , Zohar J, Mathe AA. The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder. Neuropsychopharmacology. 2012;37:350–63. doi: 10.1038/ npp.2011.230
Everitt BJ, Robbins TW. Central cholinergic systems and cognition. Annu Rev Psychol. 1997;48:649–84. doi:10.1146/ annurev.psych.48.1.649
File SE, Gonzales LE, Andrews N. Endogenous acetylcholine in the dorsal hippocampus reduces anxiety through actions on nicotinic and muscarinic1 receptors. Behav Neurosci. 1998;112:352-9. PMID:9588482
Sienkiewicz-Jarosz H, Czlonkowska AI, Siemiatkowski M, Maciejak P, Szyndler J, Plaznik Z. The effects of physostigmine and cholinergic receptor ligands on noveltyinduced neophobia. J Neural Transm. 2000;107:1403–12. doi: 10.1007/s007020070004
Aykac A, Aydın B, Cabadak H, Goren ZM. The change in muscarinic receptor subtypes in different brain regions of rats treated with fluoxetine or propranolol in a model of posttraumatic stress disorder. Behavi Brain Res 2012; 232:124-9. doi: 10.1016/j.bbr.2012.04.002
Javelot H, Weiner L, Terramorsi R, Rougeot C, Lalonde R, Messaoudi M. Efficacy of chronic antidepressant treatments in a new model of extreme anxiety in rats. Depress Res Treat 2011; 2011:1-10. doi: 10.1155/2011/531435