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Evaluation of the Effect of Prazosin Treatment on α-2c Adrenoceptor and Apoptosis Protein Levels in the Predator Scent-Induced Rat Model of Post-Traumatic Stress Disorder

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Abstract

The predator scent-induced (PSI) stress model is a rat model used to mimic post-traumatic stress disorder (PTSD) symptoms in humans. There is growing evidence that prazosin, which blocks α-1 and is approved by the FDA as an anti-hypertensive drug, can potentially be of use in the treatment of PTSD-related sleep disorders. The aim of this study was to investigate the role of prazosin treatment on behavioral parameters (freezing time, total transitions, and rearing frequency measured from the open field; anxiety index, total entries and time spent in open arms calculated from the elevated plus maze), apoptotic proteins and α-2c-AR in fear memory reconsolidation in the PSI stress rat model. We used western blot analysis to determine the effect of prazosin (0.5 mg/kg/ip) on α-2c-AR and apoptotic protein expression changes in the frontal cortex, hippocampus, and amygdala. It was determined that in the stress group, there was increased freezing time and anxiety index, and decreased rearing frequency, total transitions, total entries, and time spent in open arms compared to the control groups. Following PSI-stress, pro-apoptotic (bax) protein expression levels increased and α-2c AR and anti-apoptotic protein (bcl-2) levels decreased in investigated all brain regions. The majority of stress-induced changes were recovered with prazosin treatment. The results of our study may potentially be useful in understanding the effect of prazosin treatment, given the fact that the amygdala, frontal cortex, and hippocampus regions are affected for stress conditions.

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References

  • Adamec R, Bartoszyk GD, Burton P (2004) Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats. Eur J Pharmacol 504:65–77

    Article  PubMed  CAS  Google Scholar 

  • Arnsten AFT, Raskind MA, Taylor FB, Connor DF (2015) The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol Stress 1:89–99

    Article  PubMed  Google Scholar 

  • Aykac A, Aydın B, Cabadak H, Gören MZ (2012) The change in muscarinic receptor subtypes in different brain regions of rats treated with fluoxetine or propranolol in a post-traumatic stress disorder model. Behav Brain Res 232:124–129

    Article  PubMed  CAS  Google Scholar 

  • Aykac A, Karanlik B (2017) The expression level of muscarinic M1 receptor subtypes in different regions of rat brain. Mar Med J 30:1–7

    Article  Google Scholar 

  • Aykaç A, Gören MZ, Cabadak H (2015) Altered ratio of proapoptotic and antiapoptotic proteins in different brain regions of female rats in a model of post-traumatic stress disorder. Turk J Biochem 40:1–7

    Article  Google Scholar 

  • Bernardi RE, Lattal KM (2010) A role for alpha-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference. Behav Neurosci 124:204–210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bremner JD (2007) Functional neuroimaging in post-traumatic stress disorder. Expert Rev Neurother 7:393–405

    Article  PubMed  PubMed Central  Google Scholar 

  • Brennan PA, Keverne EB (1997) Neural mechanisms of mammalian olfactory learning. Prog Neurobiol 51:457–481

    Article  PubMed  CAS  Google Scholar 

  • Carli M, Prontera C, Samanin R (1989) Effect of 5-HT1A agonists on stress induced deficit in open field locomotor activity of rats: evidence that this model identifies anxiolytic-like activity. Neuropharmacology 28:471–476

    Article  PubMed  CAS  Google Scholar 

  • Cohen H, Matar MA, Zohar J (2013) Animal models of post-traumatic stress. 2013. Preclinical models of neurologic and psychiatric disorders. Curr Proto Neurosci 9:1–18

    Google Scholar 

  • Cohen H, Matar MA, Richter-Levin G, Zohar J (2007) The contribution of an animal model toward uncovering biological risk factors for PTSD. Ann NY Acad Sci 1071:335–350

    Article  Google Scholar 

  • Daskalakis NP, Yehuda R (2014) Principles for developing animal models of military PTSD. Eur J Psychotraumatol 5:23825

    Article  Google Scholar 

  • Ding J, Han F, Shi Y (2010) Single-prolonged stress induces apoptosis in the amygdala in a rat model of post-traumatic stress disorder. J Psychiatr Res 44:48–55

    Article  PubMed  Google Scholar 

  • Do-Monte FH, Allensworth M, Carobrez AP (2010) Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex. Behav Brain Res 211:89–95

    Article  PubMed  CAS  Google Scholar 

  • Elzinga BM, Bremner JD (2002) Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J Affect Disord 70:1–17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Girgenti MJ, Hare BD, Ghosal S, Duman RS (2017) Molecular and cellular effects of traumatic stress: implications for PTSD. Curr Psychiatry Rep 19:85

    Article  PubMed  PubMed Central  Google Scholar 

  • Hayasaka Y, Purgato M, Magni LR, Ogawa Y, Takeshima N, Cipriani A, Barbui C, Leucht S, Furukawa TA (2015) Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord. 180:179–184

  • Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, van Ommeren M, de Jong J, Seedat S, Chen H, Bisson JI (2015) Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry 206:93–100

    Article  PubMed  Google Scholar 

  • Jia Y, Han Y, Wang X, Han F (2018) Role of apoptosis in the post-traumatic stress disorder model-single prolonged stressed rats. Psychoneuroendocrinology 95:7–105

    Article  Google Scholar 

  • Kirkwood CK, Makela EH, and Wells BG (2008) Anxiety disorders II: posttraumatic stress disorder and obsessive-compulsive disorder. In: Di Piro J, Talbert R, Yee G, et al (ed) Pharmacotherapy, a pathophysiologic approach. 7th edn. New York, NY: Mc Graw-Hill Companies, Inc., pp 1179–1184

  • Kroon JA, Carobrez AP (2009) Olfactory fear conditioning paradigm in rats: effects of midazolam, propranolol or scopolamine. Neurobiol Learn Mem 91:32–40

    Article  PubMed  CAS  Google Scholar 

  • Le Dorze C, Gisquet-Verrier P (2016) Sensitivity to trauma-associated cues is restricted to vulnerable traumatized rats and reinstated after extinction by yohimbine. Behav Brain Res 313:120–134

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Far AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–327

    Article  PubMed  CAS  Google Scholar 

  • Manion ST, Gamble EH, Li H (2007) Prazosin administrated prior to inescapable stressor blocks subsequent exaggeration of acoustic startle response in rats. Pharmacol Biochem Behav 86:559–565

    Article  PubMed  CAS  Google Scholar 

  • Manoli I, Alesci S, Blackman MR, Su YA, Rennert OM, Chrousos GP (2007) Mitochondria as key components of the stress response. Trends Endocrinol Metab 8:190–198

    Article  CAS  Google Scholar 

  • Matar MA, Cohen H, Kaplan Z, Zohar J (2006) The effect of early post-stressor intervention with sertraline on behavioral responses in an animal model of posttraumatic stress disorder. Neuropsychopharmacol 31:2610–2618

    Article  CAS  Google Scholar 

  • Mazor A, Matar MA, Kaplan Z, Kozlovsky N, Zohar J, Kohen H (2009) Gender related qualitative differences in baseline and post-stress anxiety responses are not reflected in the incidence of criterion-based PTSD-like behavior patterns. World J Biol Psychiatry 10:856–869

    Article  PubMed  Google Scholar 

  • Miller LJ (2008) Prazosin for the treatment of posttraumatic stress disorder sleep disturbances. Pharmacotherapy 28:656–666

    Article  PubMed  CAS  Google Scholar 

  • Montea FH, Souza RR, Wong TT, Carobrez AP (2013) Systemic or intra-prelimbic cortex infusion of prazosin impairs fear memory reconsolidation. Behav Brain Res 244:137–141

    Article  CAS  Google Scholar 

  • Otto T, Cousens G, Herzog C (2010) Behavioral and neuropsychological foundations of olfactory fear conditioning. Behav Brain Res 110:119–128

    Article  Google Scholar 

  • Pandaranandaka J, Poonyachoti S, Kalandakanond-Thongsong S (2006) Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats. Physiol Behav 87:828–835

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, London

    Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open-closed arm entries in an elevated plus maze as measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  PubMed  CAS  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen DD, Kincaid CL, Froehlich JC (2017) Prazosin prevents increased anxiety behavior that occurs in response to stress during alcohol deprivations. Alcohol Alcohol 52:5–11

    Article  PubMed  CAS  Google Scholar 

  • Rogoz Z, Kabzinski M, Sadaj W, Rachwalska P, Gądek-Michalska A (2012) Effect of cotreatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test. Pharmacol Rep 64:1391–1399

    Article  PubMed  CAS  Google Scholar 

  • Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M (1998) Adrenergic alpha2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J Neurosci 18:3035–3042

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schoenfeld TJ, Rhee D, Martin L, Smith S, Sonti A, Padmanaban VS (2019) New neurons restore structural and behavioural abnormalities in a rat model of PTSD. Hippocampus 29:848–861

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shallcross J, Hámor P, Bechard AR, Romano M, Knackstedt L, and Schwendt M (2019) The divergent effects of CDPPB and Cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats. Front Behav Neurosci 10:13:91

  • Skelly MJ, Chappell AE, Carter E, Weiner JL (2015) Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: possible role of disrupted noradrenergic signaling. Neuropharmacol 97:149e159

    Article  CAS  Google Scholar 

  • Steven M, Hudson SM, Whiteside TE, Lorenz RA, Wargo KA (2012) Prazosin for the treatment of nightmares related to posttraumatic stress disorder: a review of the literature. Prime Care Companion. CNS Disord 14:PCC.11r01222

    Google Scholar 

  • Stone EA, Quartermain D, Lin Y, Lehmann ML (2007) Central a1-adrenergic system in behavioral activity and depression. Biochem Pharmacol 73:1063–1075

    Article  PubMed  CAS  Google Scholar 

  • Takamura N, Masuda T, Inoue T, Nakagawa S, Koyama T (2012) The effects of the co-administration of the α1-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat. Prog Neuro-Psychopharmacol Biol Psychiatry 39:107–111

    Article  CAS  Google Scholar 

  • Taylor HR, Freeman MK, Cates ME (2008) Prazosin for treatment of nightmares related to posttraumatic stress disorder. Am J Health Syst Pharm 65:716–722

    Article  PubMed  CAS  Google Scholar 

  • Terzioğlu B, Kaleli M, Aydın B, Ketenci S, Cabadak H, Gören MZ (2013) Increased noradrenaline levels in the rostral pons can be reversed by M1 antagonist in a rat model of post-traumatic stress disorder. Neurochem Res 38:1726–1733

    Article  PubMed  CAS  Google Scholar 

  • Van Liempt S, Vermetten E, Geuze E, Westenberg HG (2006) Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. Int Clin Psychopharmacol 21:193–202

    Article  PubMed  Google Scholar 

  • Wang L, Han D, Yin P, Teng K, Jianqin-Xu J, and Ma Y (2019) Decreased tryptophan hydroxylase 2 mRNA and protein expression, decreased brain serotonin concentrations, and anxiety-like behavioral changes in a rat model of simulated transport stress. Stress 1–11

  • Xiao B, Yu B, Wang HT, Han F, Shi YX (2011) Single-prolonged stress induces apoptosis by activating cytochrome C/caspase-9 pathway in a rat model of post-traumatic stress disorder. Cell Mol Neurobiol 31:37–43

    Article  PubMed  CAS  Google Scholar 

  • Yehuda R, Giller EL, Southwick SM, Lowy MT, Mason JW (1991) Hypothalamic- pituitary-adrenal dysfunction in posttraumatic stress disorder. Biol Psychiatry 30:1031–1048

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Zhou R, Li X, Ursano RJ, Li H (2006) Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: a possible mechanism for hippocampus atrophy in PTSD. Med Hypotheses 66:1205–1208

    Article  PubMed  CAS  Google Scholar 

  • Zoladz PR, Fleshner M, Diamond DM (2013) Differential effectiveness of tianeptine, clonidine and amitriptyline in blocking traumatic memory expression, anxiety and hypertension in an animal model of PTSD. Prog Neuro-Psychopharmacol Biol Psychiatry 44:1–16

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Experimental Health Sciences Research Centre, Near East University, Cyprus under Grant number SAG-2017-1-011.

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Authors and Affiliations

  1. Department of Biophysics, Faculty of Medicine, Near East University, Near East University Boulevard, 99138, Nicosia, Cyprus

    Asli Aykac

  2. Bioinformatics and Computational Research Group, DESAM Institute, Near East University, Boulevard, 99138, Nicosia, Cyprus

    Asli Aykac

  3. Department of Pharmacology, Faculty of Dentistry, Near East University, Near East University Boulevard, 99138, Nicosia, Cyprus

    Ahmet Özer Şehirli

  4. Department of Medical Pharmacology, School of Medicine, Marmara University, Başıbüyük Health Campus, Başıbüyük Road No: 9/2 Maltepe, 34854, Istanbul, Turkey

    M. Zafer Gören

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  1. Asli Aykac
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Aykac, A., Şehirli, A.Ö. & Gören, M.Z. Evaluation of the Effect of Prazosin Treatment on α-2c Adrenoceptor and Apoptosis Protein Levels in the Predator Scent-Induced Rat Model of Post-Traumatic Stress Disorder. J Mol Neurosci 70, 1120–1129 (2020). https://doi.org/10.1007/s12031-020-01518-7

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