Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine

Aslı Aykaç; Şule Öncül; Rüştü Onur

Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine

Abstract

We compared different stress conditions on brain BDNF levels, in rats exposed to social isolation test (SIT) and predator scent tests (PST). BDNF expression in the frontal cortex, hippocampus, and amygdala was compared, and effects of chronic fluoxetine (FLU) treatment were evaluated. Rats were exposed to SIT and PST for one month. FLU was given (5 mg/kg/day, ip) throughout stress procedures. Controls, stress, and treatment groups were evaluated in elevated plus maze, anxiety scores were calculated. BDNF expression was determined by Western blot. SIT and PST induced anxiety in both sexes, females had greater anxiety scores than males (p<0.05). FLU restored anxiety scores in both sexes (p<0.01) in both tests. Male and female rats exhibited reduced cortical BDNF levels in SIT (p<0.001). PST reduced cortical BDNF in females, but increased in males. Hippocampal BDNF expression was lowered in SIT (p<0.01) and PST (p<0.001) in both sexes. Female rats had 40% lower BDNF expression than males in the amygdala in SIT. FLU did not restore cortical BDNF in females in both tests, but reduced increased BDNF levels in males in PST (p<0.001). FLU did not restore reduced brain BDNF in males in the hippocampus and amygdala, but restored in hippocampus, in females. Our findings indicate that sex differences must be considered in studies related to mood disorders of animal models, and suggest that BDNF expression in different brain regions are altered differentially in a gender-dependent manner in rats. Antianxiety effect of FLU is not mediated through increasing BDNF activity in cortex in both genders. Increased BDNF in hippocampus and amygdala may reflect antidepressant effect of FLU in female rats, but not in males.

Keywords

References

[1] Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry. 2002; 3: 306–310.
[2] Duman RS, Monteggia LM. A Neurotrophic Model for Stress-Related Mood Disorders. Biol Psychiatry. 2006; 59(12): 1116-1127.
[3] Khundakar AA, Zetterström TS. Biphasic change in BDNF gene expression following antidepressant drug treatment explained by differential transcript regulation. Brain Res. 2006; 1106(1): 12-20.
[4] Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M. Alteration of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003; 54: 70-75.
[5] Smith MA, Makino S, Kvetnansky R, Post RM. Stress alters the express brain derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995; 15: 1768-1777.
[6] Nibuya M, Takahashi M, Russell DS, Duman RS. Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett. 1999; 267(2): 81-84.
[7] Roceri M, Cirulli F, Pessina C, Peretto P, Racagni G, Riva MA. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry. 2004; 55(7): 708-714.
[8] Kozlovsky N, Matar MA, Kaplan Z, Kotler M, Zohar J, Cohen H. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int J Neuropsychopharmacol. 2007; 10(6): 741-758.

[9] Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci. 2011; 31(12): 4475-4483.
[10] Martinotti G, Sepede G, Brunetti M, Ricci V, Gambi F, Chillemi E, Vellante F, Signorelli M, Pettorruso M, De Risio L, Aguglia E, Angelucci F, Caltagirone C, Di Giannantonio M. BDNF concentration and impulsiveness level in post-traumatic stress disorder. 2015; 30; 229(3): 814-818.
[11] Hashimoto K. Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF as diagnostic biomarkers for major depressive disorder and bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2015; 265(1): 83-84.
[12] Shirayama Y, Chen AC, Nakagawa S, Russell RS, Duman RS. Brain derived neurotrophic factor produced antidepressant effects in behavioral models of depression. J Neurosci. 2002; 22: 3251-3261.
[13] Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM. BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res. 1996; 710: 11-20.
[14] Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. Neurosci. 1996; 16: 2365-2372.
[15] Copella AL, Pei Q, Zetterström TSC. Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacol. 2003; 44: 903-910.
[16] Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000; 48(8): 732-739.
[17] Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA, Overholser JC, Meltzer HY, Jurjus GJ, Konick LC, Newton SS, Duman RS. Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder. J Neurosci. 2007; 27(48): 13329-13340.
[18] Mendez-David I, Tritschler L, Ali ZE, Damiens MH, Pallardy M, David DJ, Kerdine-Römer S, Gardier AM. Nrf2-signaling and BDNF: A new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression. Neurosci Lett. 2015; 597: 121-126.
[19] Carter-Snell C, Hegadoren K. Stress disorders and gender: implications for theory and research. Can J Nurs Res. 2003; 35: 34-55.
[20] Kessler R. Epidemiology of women and depression. J Affect Disord. 2003; 74(1): 5-13.
[21] Lin Y, Ter Horst GJ, Wichmann R, Bakker P, Liu A, Li X, Westenbroek C. Sex differences in the effects of acute and chronic stress and recovery after long-term stress on stress-related brain regions of rats. Cereb Cortex. 2009; 19(9): 1978-1989.
[22] Franklin TB, Perrot-Sinal TS. Sex and ovarian steroids modulate brain-derived neurotrophic factor (BDNF) protein levels in rat hippocampus under stressful and non-stressful conditions. Psychoneuroendocrinology. 2006; 31(1): 38-48.
[23] Mitic M, Simic I, Djordjevic J, Radojcic MB, Adzic M. Gender-specific effects of fluoxetine on hippocampal glucocorticoid receptor phosphorylation and behavior in chronically stressed rats. Neuropharmacology. 2013; 70: 100-611.
[24] Leser IN, Wagner S. The effects of acute social isolation on long-term social recognition memory. Neurobiol Learn Mem. 2015; 124: 97-103.
[25] Zlatkovic J, Bernardi RE, Filipovic D. Protective effect of Hsp70i against chronic social isolation stress in the rat hippocampus. J Neural Transm. 2014; 121: 3–14.
[26] Nestler EJ, Barrett M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002; 34: 13-25.
[27] McEwen B. Stress and hippocampus plasticity. Curr Opin Neurobiol. 1999; 5: 205-216.
[28] Duman RS, Malberg J, Thome J. Neural Plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999; 46: 1181-1191.
[29] Sapolsky R. Glucocorticoids and atrophy of the human hippocampus. Science. 1999; 273: 749-750.
[30] Sapolsky R. Depression, antidepressant, and the shrinking hippocampus. Proc Natl Acad Sci USA. 2001; 98: 12320-12322.
[31] Zohar J, Matar MA, Ifergane G, Kaplan Z, Cohen H. Brief post-stressor treatment with pregabalin in an animal model for PTSD: Short-term anxiolytic effects without long-term anxiogenic effect. Eur Neuropsychopharmacol. 2008; 9: 653-666.
[32] 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: 335–350.
[33] Mazor A, Michael A, Matar A, Kaplan Z, Kozlovsky N, Zohar J, Kaplan Z, 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: 856–869.
[34] Pellow S, Chopin P, File SE, Briley M. Validation of open-closed arm entries in an elevated plus maze as measure of anxiety in the rat. J Neurosci Methods. 1985; 14(3): 149-167.
[35] Cohen H, Matar MA, Zohar J. Animal Models of Post-Traumatic Stress. Preclinical Models of Neurologic and Psychiatric Disorders. Curr Protoc Neurosci. 2013; 9(45 Suppl 64): 1-18.
[36] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6nd ed. London: Academic Press, 1986.
[37] Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265-275.

Details

Primary Language

English

Subjects

Basic Pharmacology

Journal Section

Research Article

Authors

Aslı Aykaç ^*
0000-0002-4885-5070
Kuzey Kıbrıs Türk Cumhuriyeti

Şule Öncül
0000-0001-8979-836X
Türkiye

Rüştü Onur This is me
0000-0002-1931-702X
Kuzey Kıbrıs Türk Cumhuriyeti

Publication Date

June 27, 2025

Submission Date

September 29, 2017

Acceptance Date

December 23, 2017

Published in Issue

Year 2018 Volume: 22 Number: 2

IZ

https://izlik.org/JA43DF38TM

Cite

RIS / Bibtex

APA

Aykaç, A., Öncül, Ş., & Onur, R. (2025). Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine. Journal of Research in Pharmacy, 22(2), 190-198. https://izlik.org/JA43DF38TM

AMA

1.Aykaç A, Öncül Ş, Onur R. Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine. J. Res. Pharm. 2025;22(2):190-198. https://izlik.org/JA43DF38TM

Chicago

Aykaç, Aslı, Şule Öncül, and Rüştü Onur. 2025. “Social Isolation and Predator Scent Tests Alter Brain BDNF Levels Differentially According to Gender, in Rats and Effects of Fluoxetine”. Journal of Research in Pharmacy 22 (2): 190-98. https://izlik.org/JA43DF38TM.

EndNote

Aykaç A, Öncül Ş, Onur R (June 1, 2025) Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine. Journal of Research in Pharmacy 22 2 190–198.

IEEE

[1]A. Aykaç, Ş. Öncül, and R. Onur, “Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine”, J. Res. Pharm., vol. 22, no. 2, pp. 190–198, June 2025, [Online]. Available: https://izlik.org/JA43DF38TM

ISNAD

Aykaç, Aslı - Öncül, Şule - Onur, Rüştü. “Social Isolation and Predator Scent Tests Alter Brain BDNF Levels Differentially According to Gender, in Rats and Effects of Fluoxetine”. Journal of Research in Pharmacy 22/2 (June 1, 2025): 190-198. https://izlik.org/JA43DF38TM.

JAMA

1.Aykaç A, Öncül Ş, Onur R. Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine. J. Res. Pharm. 2025;22:190–198.

MLA

Aykaç, Aslı, et al. “Social Isolation and Predator Scent Tests Alter Brain BDNF Levels Differentially According to Gender, in Rats and Effects of Fluoxetine”. Journal of Research in Pharmacy, vol. 22, no. 2, June 2025, pp. 190-8, https://izlik.org/JA43DF38TM.

Vancouver

1.Aslı Aykaç, Şule Öncül, Rüştü Onur. Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine. J. Res. Pharm. [Internet]. 2025 Jun. 1;22(2):190-8. Available from: https://izlik.org/JA43DF38TM