Role of NMDA Antagonists in Animal Models of Depression
Keywords:Amantidine, Forced swim test, Imipramine, NMDA antagonists, Tail suspension test
Background: The glutamate system has been studied in depression recently. This is a different from our previous thinking, which had only focused on the levels of serotonin and norepinephrine. The glutamate system may represent a new platform for the management of depression. NMDA and AMPA are receptors for excitatory neurotransmitter, glutamate. Blocking NMDA increases the activity of another receptor, AMPA and this enhanced AMPA activity is cause for rapid antidepressant action. Amantidine and ketamine being non-competitive antagonists of NMDA receptor is evaluated for their antidepressant activity in this study.
Objectives: The objective of the study was to evaluate the antidepressant activity of NMDA antagonists, amantidine and ketamine in Swiss albino mice.
Methodology: Total of 48 (n=48) Swiss albino male mice were used. They were divided into eight groups of six mice in each group. First four groups received, normal saline 10mg/kg (control), imipramine 10mg/kg (standard) and amantidine 30 mg/kg (test drug-1) and ketamine 50mg/kg (test drug-2) per orally and evaluated for antidepressant activity by tail suspension test (TST) after sixty minutes of oral drug administration. Similarly, remaining four groups received the same drugs and evaluated for antidepressant action by forced swim test (FST) after sixty minutes of oral drug administration. Duration of immobility was observed for 6 minutes in tail suspension test and for 4 minutes in forced swim test for each mouse.
Results: Results were analyzed by ANOVA followed by Post hoc Tukey’s test. The mean immobility time for TST and FST after the administration of amantidine (30 mg/kg) was found to be 77.33± 15.05 and 95.17± 20.07 seconds respectively. Similarly, for ketamine (50mg/kg), the mean immobility time was 160.00±26.79 and 117.2±21.8 seconds respectively for TST and FST models. The amantidine and ketamine significantly reduced the immobility time in both the models of depression when compared to control (p < 0.05).
Conclusion: Non-competitive antagonists, amantidine and ketamine have significant antidepressant activity in acute models of depression.
2. Sayers J. The world health report 2001 - Mental Health: New Understanding, New Hope. Bull World Health Organ 2001; 79(11): 1085.
3. Andrade L, Caraveo A. Epidemiology of major depressive episodes: Results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys . Int J Methods Psychiatr Res 2003; 12(1): 3-21.
4. Kessler RC, Berglund P, Demler O. The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289(203): 3095-105.
5. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age of onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 2005; 62(6):617-27.
6. Murphy JM, Laird NM, Monson RR, et al. A 40-year perspective on the prevalence of depression: the Stirling County Study. Archives of General Psychiatry 2000; 57(3): 209-15.
7. Kuehner C. Gender differences in unipolar depression: An update of epidemiological findings and possible explanations. Acta Psychiatrica Scandinavica 2003; 108(3): 163-74.
8. Faster-Acting Antidepressants Closer to Becoming a Reality. NIMH. 25 July, 2007.
9. Steru L, Chermat R, Thierry B, et al. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985; 85(3):367-70.
10. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229(2): 327-36.
11. Lieberman JA, Greenhouse J, Hamer RM, et al. Comparing the effects of antidepressants: Consensus guidelines for evaluating quantitative reviews of antidepressant efficacy. Neuropsychopharmacology 2005; 30: 445-60.
12. Blier P, De Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994; 15: 230-6.
13. Trullas R, Skolnick P. Functional antagonists of the NMDA receptor complex exhibit antidepressant action. Eur J Pharmacol 1990; 185: 1-10.
14. Maj J, Rogoz Z, Skuza G, et al. The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists in the forced swimming test. Pol J Pharmacol 1992; 44: 337-46.
15. Papp P, Moryl E. Antidepressant activity of noncompetitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol 1994; 263: 1-7.
16. Paul IA, Nowak G, Layer RT, et al. Adaptation of the N-methyl-D-aspartate complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994; 269: 95-102.
17. Boyer PA, Skolnick P, Fossum LH. Chronic administration of imipramine and citalopram alters the expression of NMDA subunit mRNAs in mouse brain. J Mol Neurosci 1998; 10: 219-33.
18. Pallotta M., Segieth J, Whitton PS. Chronic but not acute clomipramine alters the effect of NMDA receptor regulation of dopamine release in the rat frontal cortex. Neurosci Lett 1999; 262: 187-90.
19. Pallotta M, Segieth J, Whitton PS. Chronic clomipramine administration reverses NMDA-evoked decreases in dopamine release in the raphe nuclei. Brain Res 1999; 823: 217-20.
20. Berman RM, Cappiello A, Annand A, et al. Antidepressant effects of ketamine in depressed patients. Bio Psychiatry 2000; 47: 351-4.
21. Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry 1999; 32: 47-55.
22. Rogoz Z, Skuza G, Maj J, et al. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 2002; 42: 1024-30.
23. Rogoz Z, Skuza G, Kusmidern M, et al. Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioural and Pharmacokinetic Studies Polish J Pharmacol 2004; 56: 179-85.
24. Owen JCE, Whitton PS. Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats. British Journal of Pharmacology 2005; 145: 587-92.
25. Eltze M. Multiple mechanisms of action: the pharmacological profile of budipine. J Neural Trans Suppl 1999; 56: 83-105.
26. Fisher A, Starr MS. Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain. Brain Res 2000; 868: 268-74.
27. Altagracia M, Rojas P, Kravzov J, et al. Amantadine enhances dopamine and serotonin turnover in the MPTP model of Parkinson’s disease. Proc West Pharmacol Soc 1993; 36: 289-91.
28. Rogóz Z, Kubera M, Rogóz K, et al. Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test. Pharmacological Reports 2009; 61: 1050-60.
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