Author(s):
Ibrahim M.K., Tikamdas R., Kamal M., Nouh, R.A., Sayed M.
Email(s):
helmy.mostafa@bue.edu.eg
DOI:
10.5958/0974-360X.2020.01053.7
Address:
Ibrahim M.K.1, Tikamdas R.2,4, Kamal M.2,3, Nouh, R.A.4, Sayed M.2,4
1Department of Developmental Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Cairo.
2Center of Drug Research and Development (CDRD), College of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Egypt.
3Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Egypt.
4Department of Clinical Pharmacy Practice, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Egypt.
*Corresponding Author
Published In:
Volume - 13,
Issue - 12,
Year - 2020
ABSTRACT:
Objective: To examine the impact of exogenous testosterone undecanoate (TU) on chronic stress-induced behavioral changes of sensory contact model in adolescent male Swiss Albino mice. Design: Stress was induced by sensory contact model (SCM) for 12 consecutive days. Defeated mice were randomly assigned to control group (vehicle), testosterone undecanoate (100mg/Kg) (TU 100) or testosterone undecanoate (500mg/Kg) (TU 500) given intramuscular once for 45 days administered 2 hours after the last SCM session. Results: SCM significantly reduced distance traveled, time spent in the center, average speed in the open field test compared to negative control group. In addition, SCM significantly reduced preference index of defeated group in the NOR test, time spent in the open arms in the EPM test, reduced escape time and time in the quadrant in Morris water maze test (MWM) when compared to the negative control group.SCM significantly reduced the mRNA expression of CREB in the hippocampus of defeated group when compared to the negative control group. In the open field test, TU 500 treatment showed a significant increase in both distance traveled and average speed compared to the defeated group, while TU 100 treatment did have an anxiolytic effect indicated by the significantly increased time spent in the center and the significantly reduced time spent in the corner and the significantly reduced immobility time when compared to the defeated group. Both TU 100 and TU 500 did improve the retention memory indicated by the significant increase in the preference index compared to the defeated group in the NOR test. In the EPM test, both TU 100 and TU 500 did show an anxiolytic effect through a significant increase in the time spent in the open arms and a significant reduction in the time spent in the closed arms compared to the defeated group. In MWM, both TU 100 and TU 500 showed a significant improvement in learning memory as indicated by a significant reduction in the escape time and a significant increase in the time spent in the target quadrant on the probe day. Interestingly, TU 500 treatment showed a significant increase in CREB relative mRNA expression in the prefrontal cortex region compared to both defeated and negative control groups. Conclusion: Exogenous testosterone administration ameliorated some age-related neurobehavioral responses after exposure to chronic social defeat; however, more studies are needed to clarify the mechanisms that underlie them.
Cite this article:
Ibrahim M.K., Tikamdas R., Kamal M., Nouh, R.A., Sayed M. Testosterone Undecanoate effects on behavior and Cognitive Functions in male swiss Albino mice exposed to Chronic Social Defeat. Research J. Pharm. and Tech. 2020; 13(12):6041-6049. doi: 10.5958/0974-360X.2020.01053.7
Cite(Electronic):
Ibrahim M.K., Tikamdas R., Kamal M., Nouh, R.A., Sayed M. Testosterone Undecanoate effects on behavior and Cognitive Functions in male swiss Albino mice exposed to Chronic Social Defeat. Research J. Pharm. and Tech. 2020; 13(12):6041-6049. doi: 10.5958/0974-360X.2020.01053.7 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2020-13-12-68
REFERENCES:
1. Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol. 2007;58:145-73.
2. Buwalda B, Geerdink M, Vidal J, Koolhaas JM. Social behavior and social stress in adolescence: a focus on animal models. Neurosci Biobehav Rev. 2011;35(8):1713-21.
3. Buwalda B, Kole MH, Veenema AH, Huininga M, de Boer SF, Korte SM, et al. Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neurosci Biobehav Rev. 2005;29(1):83-97.
4. Schneider M. Adolescence as a vulnerable period to alter rodent behavior. Cell Tissue Res. 2013;354(1):99-106.
5. Paus T, Keshavan M, Giedd JN. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci. 2008;9(12):947-57.
6. Venzala E, García-García AL, Elizalde N, Delagrange P, Tordera RM. Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors. Psychopharmacology (Berl). 2012;224(2):313-25.
7. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR J. 2014;55(2):221-32.
8. Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417-63.
9. Sterlemann V, Ganea K, Liebl C, Harbich D, Alam S, Holsboer F, et al. Long-term behavioral and neuroendocrine alterations following chronic social stress in mice: implications for stress-related disorders. Horm Behav. 2008;53(2):386-94.
10. Hollis F, Wang H, Dietz D, Gunjan A, Kabbaj M. The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague-Dawley rats. Psychopharmacology (Berl). 2010;211(1):69-77.
11. McHenry J, Carrier N, Hull E, Kabbaj M. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol. 2014;35(1):42-57.
12. Celec P, Ostatníková D, Hodosy J. On the effects of testosterone on brain behavioral functions. Front Neurosci. 2015;9:12.
13. Khera M. Patients with testosterone deficit syndrome and depression. Arch Esp Urol. 2013;66(7):729-36.
14. Aikey JL, Nyby JG, Anmuth DM, James PJ. Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Horm Behav. 2002;42(4):448-60.
15. van Honk J, Peper JS, Schutter DJ. Testosterone reduces unconscious fear but not consciously experienced anxiety: implications for the disorders of fear and anxiety. Biol Psychiatry. 2005;58(3):218-25.
16. Pope HG, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(1):105-11.
17. Miller KK, Perlis RH, Papakostas GI, Mischoulon D, Losifescu DV, Brick DJ, et al. Low-dose transdermal testosterone augmentation therapy improves depression severity in women. CNS Spectr. 2009;14(12):688-94.
18. Linn MC, Petersen AC. Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Dev. 1985;56(6):1479-98.
19. Silverman I, Kastuk D, Choi J, Phillips K. Testosterone levels and spatial ability in men. Psychoneuroendocrinology. 1999;24(8):813-22.
20. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001;57(1):80-8.
21. Postma A, Meyer G, Tuiten A, van Honk J, Kessels RP, Thijssen J. Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology. 2000;25(6):563-75.
22. Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005;64(12):2063-8.
23. Cherrier MM, Matsumoto AM, Amory JK, Johnson M, Craft S, Peskind ER, et al. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology. 2007;32(1):72-9.
24. Callies F, Kollenkirchen U, von zur Mühlen C, Tomaszewski M, Beer S, Allolio B. Testosterone undecanoate: a useful tool for testosterone administration in rats. Exp Clin Endocrinol Diabetes. 2003;111(4):203-8.
25. Carlezon WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci. 2005;28(8):436-45.
26. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16(7):2365-72.
27. Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci. 2000;20(11):4030-6.
28. Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS. Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry. 2001;49(9):753-62.
29. Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci. 2001;21(18):7397-403.
30. Barrot M, Olivier JD, Perrotti LI, DiLeone RJ, Berton O, Eisch AJ, et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci U S A. 2002;99(17):11435-40.
31. Pandey SC, Roy A, Zhang H. The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol Clin Exp Res. 2003;27(3):396-409.
32. Kudryavtseva NN, Smagin DA, Kovalenko IL, Vishnivetskaya GB. Repeated positive fighting experience in male inbred mice. Nat Protoc. 2014;9(11):2705-17.
33. Weiss IC, Pryce CR, Jongen-Rêlo AL, Nanz-Bahr NI, Feldon J. Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. Behav Brain Res. 2004;152(2):279-95.
34. Hale G, Good M. Impaired visuospatial recognition memory but normal object novelty detection and relative familiarity judgments in adult mice expressing the APPswe Alzheimer's disease mutation. Behav Neurosci. 2005;119(4):884-91.
35. Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res. 2010;215(2):244-54.
36. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988;31(1):47-59.
37. Bourin M, Petit-Demoulière B, Dhonnchadha BN, Hascöet M. Animal models of anxiety in mice. Fundam Clin Pharmacol. 2007;21(6):567-74.
38. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1(2):848-58.
39. Chiu K, Lau WM, Lau HT, So KF, Chang RC. Micro-dissection of rat brain for RNA or protein extraction from specific brain region. J Vis Exp. 2007(7):269.
40. Hodosy J, Zelmanová D, Majzúnová M, Filová B, Malinová M, Ostatníková D, et al. The anxiolytic effect of testosterone in the rat is mediated via the androgen receptor. Pharmacol Biochem Behav. 2012;102(2):191-5.
41. Filova B, Malinova M, Babickova J, Tothova L, Ostatnikova D, Celec P, et al. Effects of testosterone and estradiol on anxiety and depressive-like behavior via a non-genomic pathway. Neurosci Bull. 2015;31(3):288-96.
42. Sinclair D, Purves-Tyson TD, Allen KM, Weickert CS. Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain. Psychopharmacology (Berl). 2014;231(8):1581-99.
43. al-Khatib IM, Dökmeci I, Fujiwara M. Differential role of nucleus accumbens and caudate-putamen in mediating the effect of nomifensine and methamphetamine on ambulation and rearing of rats in the open-field test. Jpn J Pharmacol. 1995;67(1):69-77.
44. Zhang L, Chang YH, Feldman AN, Ma W, Lahjouji F, Barker JL, et al. The expression of GABA(A) receptor alpha2 subunit is upregulated by testosterone in rat cerebral cortex. Neurosci Lett. 1999;265(1):25-8.
45. Cherney ID, Brabec CM, Runco DV. Mapping out spatial ability: sex differences in way-finding navigation. Percept Mot Skills. 2008;107(3):747-60.
46. Naghdi N, Oryan S, Etemadi R. The study of spatial memory in adult male rats with injection of testosterone enanthate and flutamide into the basolateral nucleus of the amygdala in Morris water maze. Brain Res. 2003;972(1-2):1-8.
47. Ackermann S, Spalek K, Rasch B, Gschwind L, Coynel D, Fastenrath M, et al. Testosterone levels in healthy men are related to amygdala reactivity and memory performance. Psychoneuroendocrinology. 2012;37(9):1417-24.
48. Spritzer MD, Daviau ED, Coneeny MK, Engelman SM, Prince WT, Rodriguez-Wisdom KN. Effects of testosterone on spatial learning and memory in adult male rats. Horm Behav. 2011;59(4):484-96.
49. Leranth C, Hajszan T, MacLusky NJ. Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats. J Neurosci. 2004;24(2):495-9.
50. Fernández-Guasti A, Martínez-Mota L. Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors. Psychoneuroendocrinology. 2005;30(8):762-70.
51. Rocha VM, Calil CM, Ferreira R, Moura MJ, Marcondes FK. Influence of anabolic steroid on anxiety levels in sedentary male rats. Stress. 2007;10(4):326-31.
52. Barco A, Pittenger C, Kandel ER. CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets. 2003;7(1):101-14.
53. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79(1):59-68.
54. Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron. 2002;34(3):447-62.
55. Josselyn SA, Shi C, Carlezon WA, Neve RL, Nestler EJ, Davis M. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J Neurosci. 2001;21(7):2404-12.
56. Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, et al. Upregulation of CREB-mediated transcription enhances both short- and long-term memory. J Neurosci. 2011;31(24):8786-802.
57. Gass P, Riva MA. CREB, neurogenesis and depression. Bioessays. 2007;29(10):957-61.
58. Bilbao A, Rieker C, Cannella N, Parlato R, Golda S, Piechota M, et al. CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects. Front Behav Neurosci. 2014;8:212.
59. Valverde O, Mantamadiotis T, Torrecilla M, Ugedo L, Pineda J, Bleckmann S, et al. Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice. Neuropsychopharmacology. 2004;29(6):1122-33.
60. Vogt MA, Inta D, Luoni A, Elkin H, Pfeiffer N, Riva MA, et al. Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits. Front Behav Neurosci. 2014;8:407.
61. Barrot M, Wallace DL, Bolaños CA, Graham DL, Perrotti LI, Neve RL, et al. Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens. Proc Natl Acad Sci U S A. 2005;102(23):8357-62.
62. Kerner B, Rao AR, Christensen B, Dandekar S, Yourshaw M, Nelson SF. Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways. Front Psychiatry. 2013;4:154.