Effect of aripiprazole and improved living conditions on behavioral manifestations and neurogenic markers expression in an animal model of PTSD

Osacka, Jana; Horvathova, Lubica; Dziewiczova, Lila; Mifkovic, Andrej; Kiss, Alexander; Tillinger, Andrej

doi:10.2478/enr-2025-0021

Abstract

Objective. Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop after exposure to a severe traumatic event and is connected with behavioral changes and adult neurogenesis impairment. Atypical antipsychotics including aripiprazole (ARI) or enriched environment can ameliorate disturbances connected to PTSD. This study was aimed to reveal whether ARI treatment supplemented by improved living conditions, i.e. toy rotation (TR), will ameliorate behavioral outcomes and reverse assumed changes in neurogenesis more effectively than sole ARI treatment in a single prolonged stress (SPS) animal model of PTSD.

Methods. Adult male Sprague-Dawley rats weighing 176–200 g were randomly assigned to 5 experimental groups: (1) VEH – control non-stressed animals injected with vehicle (VEH, 2% Tween 20 in the saline); (2) SPS – animals exposed to SPS injected with VEH; (3) SPS+ARI – SPS animals injected with ARI (5 mg/kg in VEH); (4) SPS+TR – SPS animals exposed to TR and injected with VEH; (5) SPS+ARI+TR – SPS animals exposed to TR and injected with ARI. Animals in TR groups were housed in the standard cages with two toys per cage, which were replaced every other day. Elevated plus maze (EPM), open field (OF), and novel object recognition test (NOR) were used to assess the anxiety-like behavior and learning/memory. Changes in gene and protein expression of selected neurogenic markers (BDNF, GFAP, Sox2, DCX, NeuN) and transcription factors (ΔFosB, pCREB) in the subventricular zone (SVZ) and the gyrus dentatus (GD) of the hippocampus were determined by semi-quantitative real-time PCR and immunohistochemistry, respectively.

Results. SPS animals showed increased anxiety-like behavior that was suppressed by TR and ARI+TR treatment combination. Although SPS did not affect the expression of studied neurogenic markers, ARI treatment increased the expression of doublecortin in the SVZ and TR increased expression of NeuN in the GD of PTSD-like animals. TR enhanced ARI effect on NeuN expression in the SVZ. SPS induced increase of ΔFosB positive cells, which was reduced by ARI+TR complementary treatment.

Conclusions. Obtained results indicate that TR, in contrary to ARI, suppressed the anxiety-like behavior in PTSD-like animals. SPS does not affect the neurogenic markers expression in the SVZ or GD, but ARI and TR or their combination seems to increase the survival of the newborn cells.

References

Acosta SA, Diamond DM, Wolfe S, Tajiri N, Shinozuka K, Ishikawa H, Hernandez DG, Sanberg PR, Kaneko Y, Borlongan CV. Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury. PLoS One 8, e81585, 2013.
Search in Google Scholar Back to article
American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM- 5™ (5th ed.). American Psychiatric Publishing, Inc, 2013.
Search in Google Scholar Back to article
Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cognitive Processing 13, 93–110, 2012.
Search in Google Scholar Back to article
Benarroch EE. Adult neurogenesis in the dentate gyrus: general concepts and potential implications. Neurology 81, 1443–1452, 2013.
Search in Google Scholar Back to article
Britnell SR, Jackson AD, Brown JN, Capehart BP. Aripiprazole for post-traumatic stress disorder: A systematic review. Clin Neuropharmacol 40, 273–278, 2017.
Search in Google Scholar Back to article
Carli M, Aringhieri S, Kolachalam S, Longoni B, Grenno G, Rossi M, Gemignani A, Fornai F, Maggio R, Scarselli M. Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders? Current Neuropharmacol 19, 1640–1660, 2021.
Search in Google Scholar Back to article
Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ. DeltaFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes. Neuropsychopharmacology 39, 538–544, 2014.
Search in Google Scholar Back to article
Eagle AL, Fitzpatrick CJ, Perrine SA. Single prolonged stress impairs social and object novelty recognition in rats. Behav Brain Res 256, 591–597, 2013.
Search in Google Scholar Back to article
Fabianova K, Zavodska M, Racek A, Angelidis A, Martoncikova M, Racekova E. Analysis of Fos expression in the rat olfactory neurogenic region following single exposure to maternal separation during different neonatal stages. Gen Physiol Biophysics 37, 275–283, 2018.
Search in Google Scholar Back to article
Fujikawa R, Ramsaran AI, Guskjolen A, de la Parra J, Zou Y, Mocle AJ, Josselyn SA, Frankland PW. Neurogenesisdependent remodeling of hippocampal circuits reduces PTSD-like behaviors in adult mice. Mol Psychiatry 29, 3316–3329, 2024.
Search in Google Scholar Back to article
Gasparyan A, Navarro D, Navarrete F, Manzanares J. Pharmacological strategies for post-traumatic stress disorder (PTSD): From animal to clinical studies. Neuropharmacology 218, 109211, 2022.
Search in Google Scholar Back to article
Gomes-Leal W. Adult hippocampal neurogenesis and affective disorders: new neurons for psychic well-being. Front Neurosci 15, 594448, 2021.
Search in Google Scholar Back to article
Gronska-Peski M, Goncalves JT, Hebert JM. Enriched environment promotes adult hippocampal neurogenesis through FGFRs. J Neurosci 41, 2899–2910, 2021.
Search in Google Scholar Back to article
Hendriksen H, Bink DI, Daniels EG, Pandit R, Piriou C, Slieker R, Westphal KG, Olivier B, Oosting RS. Re-exposure and environmental enrichment reveal NPY-Y1 as a possible target for post-traumatic stress disorder. Neuropharmacology 63, 733–742, 2012.
Search in Google Scholar Back to article
Chen AT, Nasrallah HA. Neuroprotective effects of the second generation antipsychotics. Schizophr Res 208, 1–7, 2019.
Search in Google Scholar Back to article
Chen L, Liu K, Wang Y, Liu N, Yao M, Hu J, Wang G, Sun Y, Pan J. Phosphodiesterase-2 inhibitor reverses posttraumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway. Eur J Pharmacol 891, 173768, 2021.
Search in Google Scholar Back to article
Chikama K, Yamada H, Tsukamoto T, Kajitani K, Nakabeppu Y, Uchimura N. Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse. Brain Res 1676, 77–82, 2017.
Search in Google Scholar Back to article
Chiu HTS, Low DCW, Chan AHT, Meiser-Stedman R. Relationship between anxiety sensitivity and post-traumatic stress symptoms in trauma-exposed adults: A meta-analysis. J Anxiety Dis 103, 102857, 2024.
Search in Google Scholar Back to article
Iqbal J, Huang GD, Shen D, Xue YX, Yang M, Jia XJ. Single prolonged stress induces behavior and transcriptomic changes in the medial prefrontal cortex to increase susceptibility to anxiety-like behavior in rats. Front Psych 15, 1472194, 2024.
Search in Google Scholar Back to article
Kusumi I, Boku S, Takahashi Y. Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis. Psych Clin Neurosci 69, 243–258, 2015.
Search in Google Scholar Back to article
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408, 2001.
Search in Google Scholar Back to article
Lisieski MJ, Eagle AL, Conti AC, Liberzon I, Perrine SA. Single-prolonged stress: a review of two decades of progress in a rodent model of post-traumatic stress disorder. Front Psych 9, 196, 2018.
Search in Google Scholar Back to article
Mackenzie L, Nalivaiko E, Beig MI, Day TA, Walker FR. Ability of predator odour exposure to elicit conditioned versus sensitised post traumatic stress disorder-like behaviours, and forebrain deltaFosB expression, in rats. Neuroscience 169, 733–742, 2010.
Search in Google Scholar Back to article
Melani R, Chelini G, Cenni MC, Berardi N. Enriched environment effects on remote object recognition memory. Neuroscience 352, 296–305, 2017.
Search in Google Scholar Back to article
Nestler EJ. ΔFosB: a transcriptional regulator of stress and antidepressant responses. Eur J Pharmacol 753, 66–72, 2015.
Search in Google Scholar Back to article
Nestler EJ, Barrot M, Self DW. DeltaFosB: a sustained molecular switch for addiction. Proc Natl Acad Sci USA 98, 11042–11046, 2001.
Search in Google Scholar Back to article
Palkovits M, Brownstein M. Maps and guide to microdissection of the rat brain. Elsevier Science, New York, 1988.
Search in Google Scholar Back to article
Peng Z, Zhang R, Wang H, Chen Y, Xue F, Wang L, Yang F, Liu L, Kuang F, Tan Q. Ziprasidone ameliorates anxietylike behaviors in a rat model of PTSD and up-regulates neurogenesis in the hippocampus and hippocampusderived neural stem cells. Behav Brain Res 244, 18, 2013.
Search in Google Scholar Back to article
Polimanti R, Wendt FR. Posttraumatic stress disorder: from gene discovery to disease biology. Psychol Med 51, 2178–2188, 2021.
Search in Google Scholar Back to article
Rief W, Barsky AJ, Bingel U, Doering BK, Schwarting R, Wohr M, Schweiger U. Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions. Neurosci Biobehav Rev 60, 51–64, 2016.
Search in Google Scholar Back to article
Serova LI, Nwokafor C, Van Bockstaele EJ, Reyes BAS, Lin X, Sabban EL. Single prolonged stress PTSD model triggers progressive severity of anxiety, altered gene expression in locus coeruleus and hypothalamus and effected sensitivity to NPY. Eur Neuropsychopharmacol 29, 482–492, 2019.
Search in Google Scholar Back to article
Schmeltzer SN, Vollmer LL, Rush JE, Weinert M, Dolgas CM, Sah R. History of chronic stress modifies acute stressevoked fear memory and acoustic startle in male rats. Stress 18. 244–253, 2015.
Search in Google Scholar Back to article
Schoenfeld TJ, Rhee D, Martin L, Smith JA, Sonti AN, Padmanaban V, Cameron HA. New neurons restore structural and behavioral abnormalities in a rat model of PTSD. Hippocampus 29, 848–861, 2019.
Search in Google Scholar Back to article
Sun XR, Zhang H, Zhao HT, Ji MH, Li HH, Wu J, Li KY, Yang JJ. Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder. Behav Brain Res 312, 84–92, 2016.
Search in Google Scholar Back to article
Takahashi T, Shimizu K, Shimazaki K, Toda H, Nibuya M. Environmental enrichment enhances autophagy signaling in the rat hippocampus. Brain Res 1592, 113–123, 2014.
Search in Google Scholar Back to article
Tanichi M, Toda H, Shimizu K, Koga M, Saito T, Enomoto S, Boku S, Asai F, Mitsui Y, Nagamine M, Fujita M, Yoshino A. Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task. Biochem Biophys Res Commun 501, 307–312, 2018.
Search in Google Scholar Back to article
Velasco ER, Florido A, Flores A, Senabre E, Gomez-Gomez A, Torres A, Roca A, Norrholm S, Newman EL, Das P, Ross RA, Lori A, Pozo OJ, Ressler KJ, Garcia-Esteve LL, Jovanovic T, Andero R. PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus. Nat Commun 13, 4374, 2022.
Search in Google Scholar Back to article
Wislowska-Stanek A, Lehner M, Tomczuk F, Kolosowska K, Krzasnik P, Turzynska D, Skorzewska A. The role of the dorsal hippocampus in resistance to the development of posttraumatic stress disorder-like behaviours. Behav Brain Res 438, 114185, 2023.
Search in Google Scholar Back to article
Yin JB, Liu HX, Shi W, Ding T, Hu HQ, Guo HW, Jin S, Wang XL, Zhang T, Lu YC, Cao BZ. Various BDNF administrations attenuate SPS-induced anxiety-like behaviors. Neurosci Lett 788, 136851, 2022.
Search in Google Scholar Back to article
Yoneyama M, Hasebe S, Kawamoto N, Shiba T, Yamaguchi T, Kikuta M, Shuto M, Ogita K. Beneficial in vivo effect of aripiprazole on neuronal regeneration following neuronal loss in the dentate gyrus: evaluation using a mouse model of trimethyltin-induced neuronal loss/self-repair in the dentate gyrus. J Pharmacol Sci 124, 99–111, 2014.
Search in Google Scholar Back to article
Zhou CH, Xue F, Xue SS, Sang HF, Liu L, Wang Y, Cai M, Zhang ZJ, Tan QR, Wang HN, Peng ZW. Electroacupuncture pretreatment ameliorates PTSD-like behaviors in rats by enhancing hippocampal neurogenesis via the Keap1/Nrf2 antioxidant signaling pathway. Front Cell Neurosci 13, 275, 2019.
Search in Google Scholar Back to article

Effect of aripiprazole and improved living conditions on behavioral manifestations and neurogenic markers expression in an animal model of PTSD

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