Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Cytisine, a Partial Agonist of α4β2 Nicotinic Acetylcholine Receptors, Reduced Unpredictable Chronic Mild Stress-Induced Depression-Like Behaviors

  • Han, Jing (Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University) ;
  • Wang, Dong-sheng (Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University) ;
  • Liu, Shui-bing (Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University) ;
  • Zhao, Ming-gao (Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University)
  • Received : 2015.07.28
  • Accepted : 2015.10.07
  • Published : 2016.05.01
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Abstract

Cytisine (CYT), a partial agonist of ${\alpha}4{\beta}2-nicotinic$ receptors, has been used for antidepressant efficacy in several tests. Nicotinic receptors have been shown to be closely associated with depression. However, little is known about the effects of CYT on the depression. In the present study, a mouse model of depression, the unpredictable chronic mild stress (UCMS), was used to evaluate the activities of CYT. UCMS caused significant depression-like behaviors, as shown by the decrease of total distances in open field test, and the prolonged duration of immobility in tail suspension test and forced swimming test. Treatment with CYT for two weeks notably relieved the depression-like behaviors in the UCMS mice. Next, proteins related to depressive disorder in the brain region of hippocampus and amygdala were analyzed to elucidate the underlying mechanisms of CYT. CYT significantly reversed the decreases of 5-HT1A, BDNF, and mTOR levels in the hippocampus and amygdala. These results imply that CYT may act as a potential anti-depressant in the animals under chronic stress.

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References

  1. Abelaira, H. M., Reus, G. Z., Neotti, M. V. and Quevedo, J. (2014) The role of mTOR in depression and antidepressant responses. Life Sci. 101, 10-14. https://doi.org/10.1016/j.lfs.2014.02.014
  2. Arias, H. R., Rosenberg, A., Targowska-Duda, K. M., Feuerbach, D., Jozwiak, K., Moaddel, R. and Wainer, I. W. (2010) Tricyclic antidepressants and mecamylamine bind to different sites in the human alpha4beta2 nicotinic receptor ion channel. Int. J. Biochem. Cell Biol. 42, 1007-1018. https://doi.org/10.1016/j.biocel.2010.03.002
  3. Bell, R. L., Eiler, B. J., 2nd, Cook, J. B. and Rahman, S. (2009) Nicotinic receptor ligands reduce ethanol intake by high alcohol-drinking HAD-2 rats. Alcohol 43, 581-592. https://doi.org/10.1016/j.alcohol.2009.09.027
  4. Bergami, M. and Berninger, B. (2012) A fight for survival: the challenges faced by a newborn neuron integrating in the adult hippocampus. Dev. Neurobiol. 72, 1016-1031. https://doi.org/10.1002/dneu.22025
  5. Cahill, K., Stevens, S., Perera, R. and Lancaster, T. (2013) Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst. Rev. 5, CD009329.
  6. Cheeta, S., Irvine, E. E., Kenny, P. J. and File, S. E. (2001) The dorsal raphe nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology (Berl.) 155, 78-85. https://doi.org/10.1007/s002130100681
  7. Damaj, M. I., Kao, W. and Martin, B. R. (2003) Characterization of spontaneous and precipitated nicotine withdrawal in the mouse. J. Pharmacol. Exp. Ther. 307, 526-534. https://doi.org/10.1124/jpet.103.054908
  8. Duman, R. S. and Voleti, B. (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 35, 47-56. https://doi.org/10.1016/j.tins.2011.11.004
  9. El Yacoubi, M., Bouali, S., Popa, D., Naudon, L., Leroux-Nicollet, I., Hamon, M., Costentin, J., Adrien, J. and Vaugeois, J. M. (2003) Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc. Natl. Acad. Sci. U.S.A. 100, 6227-6232. https://doi.org/10.1073/pnas.1034823100
  10. Fryer, J. D. and Lukas, R. J. (1999) Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function. J. Neurochem. 72, 1117-1124.
  11. Glassman, A. H., Helzer, J. E., Covey, L. S., Cottler, L. B., Stetner, F., Tipp, J. E. and Johnson, J. (1990) Smoking, smoking cessation, and major depression. JAMA 264, 1546-1549. https://doi.org/10.1001/jama.1990.03450120058029
  12. Gotti, C., Riganti, L., Vailati, S. and Clementi, F. (2006) Brain neuronal nicotinic receptors as new targets for drug discovery. Curr. Pharm. Des. 12, 407-428. https://doi.org/10.2174/138161206775474486
  13. Hennings, E. C., Kiss, J. P. and Vizi, E. S. (1997) Nicotinic acetylcholine receptor antagonist effect of fluoxetine in rat hippocampal slices. Brain Res. 759, 292-294. https://doi.org/10.1016/S0006-8993(97)00343-0
  14. Hogg, R. C., Raggenbass, M. and Bertrand, D. (2003) Nicotinic acetylcholine receptors: from structure to brain function. Rev. Physiol. Biochem. Pharmacol. 147, 1-46.
  15. Janowsky, D. S., el-Yousef, M. K., Davis, J. M. and Sekerke, H. J. (1972) A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2, 632-635.
  16. Koo, J. W. and Duman, R. S. (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl. Acad. Sci. U.S.A. 105, 751-756. https://doi.org/10.1073/pnas.0708092105
  17. Lopez-Valdes, H. E. and Garcia-Colunga, J. (2001) Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake. Mol. Psychiatry 6, 511-519. https://doi.org/10.1038/sj.mp.4000885
  18. Lukas, R. J., Changeux, J. P., Le Novère, N., Albuquerque, E. X., Balfour, D. J., Berg, D. K., Bertrand, D., Chiappinelli, V. A., Clarke, P. B., Collins, A. C., Dani, J. A., Grady, S. R., Kellar, K. J., Lindstrom, J. M., Marks, M. J., Quik, M., Taylor, P. W. and Wonnacott, S. (1999) International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol. Rev. 51, 397-401.
  19. Ma, Z., Strecker, R. E., McKenna, J. T., Thakkar, M. M., McCarley, R. W. and Tao, R. (2005) Effects on serotonin of (-)nicotine and dimethylphenylpiperazinium in the dorsal raphe and nucleus accumbens of freely behaving rats. Neuroscience 135, 949-958. https://doi.org/10.1016/j.neuroscience.2005.06.074
  20. Millar, N. S. (2003) Assembly and subunit diversity of nicotinic acetylcholine receptors. Biochem. Soc. Trans. 31, 869-874. https://doi.org/10.1042/bst0310869
  21. Mineur, Y. S., Einstein, E. B., Bentham, M. P., Wigestrand, M. B., Blakeman, S., Newbold, S. A. and Picciotto, M. R. (2015) Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology 40, 938-946. https://doi.org/10.1038/npp.2014.269
  22. Nasca, C., Xenos, D., Barone, Y., Caruso, A., Scaccianoce, S., Matrisciano, F., Battaglia, G., Mathe, A. A., Pittaluga, A., Lionetto, L., Simmaco, M. and Nicoletti, F. (2013) L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc. Natl. Acad. Sci. U.S.A. 110, 4804-4809. https://doi.org/10.1073/pnas.1216100110
  23. Philip, N. S., Carpenter, L. L., Tyrka, A. R. and Price, L. H. (2010) Nicotinic acetylcholine receptors and depression: a review of the preclinical and clinical literature. Psychopharmacology (Berl.) 212, 1-12. https://doi.org/10.1007/s00213-010-1932-6
  24. Philip, N. S., Carpenter, L. L., Tyrka, A. R. and Price, L. H. (2012) The nicotinic acetylcholine receptor as a target for antidepressant drug development. ScientificWorldJournal 2012, 104105.
  25. Picciotto, M. R., Zoli, M., Léna, C., Bessis, A., Lallemand, Y., Le Novere, N., Vincent, P., Pich, E. M., Brûlet, P. and Changeux, J. P. (1995) Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374, 65-67. https://doi.org/10.1038/374065a0
  26. Picciotto, M. R., Zoli, M., Rimondini, R., Léna, C., Marubio, L. M., Pich, E. M., Fuxe, K. and Changeux, J. P. (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173-177. https://doi.org/10.1038/34413
  27. Radchenko, E. V., Dravolina, O. A. and Bespalov, A. Y. (2015) Agonist and antagonist effects of cytisine in vivo. Neuropharmacology 95, 206-214. https://doi.org/10.1016/j.neuropharm.2015.03.019
  28. Rahman, S. (2015) Targeting brain nicotinic acetylcholine receptors to treat major depression and co-morbid alcohol or nicotine addiction. CNS Neurol. Disord. Drug Targets 14, 647-653. https://doi.org/10.2174/1871527314666150429112954
  29. Sajja, R. K. and Rahman, S. (2013) Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of DeltaFosB in mice. Alcohol 47, 299-307. https://doi.org/10.1016/j.alcohol.2013.02.003
  30. Salin-Pascual, R. J., de la Fuente, J. R., Galicia-Polo, L. and Drucker- Colin, R. (1995) Effects of transderman nicotine on mood and sleep in nonsmoking major depressed patients. Psychopharmacology (Berl.) 121, 476-479. https://doi.org/10.1007/BF02246496
  31. Salin-Pascual, R. J., Rosas, M., Jimenez-Genchi, A., Rivera-Meza, B. L. and Delgado-Parra, V. (1996) Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression. J. Clin. Psychiatry 57, 387-389.
  32. Schmidt, B. L., Tambeli, C. H., Gear, R. W. and Levine, J. D. (2001) Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens. Neuroscience 106, 129-136. https://doi.org/10.1016/S0306-4522(01)00264-0
  33. Semba, J., Mataki, C., Yamada, S., Nankai, M. and Toru, M. (1998) Antidepressantlike effects of chronic nicotine on learned helplessness paradigm in rats. Biol. Psychiatry 43, 389-391. https://doi.org/10.1016/S0006-3223(97)00477-0
  34. Seth, P., Cheeta, S., Tucci, S. and File, S. E. (2002) Nicotinic--serotonergic interactions in brain and behaviour. Pharmacol. Biochem. Behav. 71, 795-805. https://doi.org/10.1016/S0091-3057(01)00715-8
  35. Tutka, P. and Zatoński, W. (2006) Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic efficacy. Pharmacol. Rep. 58, 777-798.
  36. Wang, W., Lu, Y., Xue, Z., Li, C., Wang, C., Zhao, X., Zhang, J., Wei, X., Chen, X., Cui, W., Wang, Q. and Zhou, W. (2015) Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice. Neuroscience 285, 281-291. https://doi.org/10.1016/j.neuroscience.2014.11.025
  37. Willner, P., Towell, A., Sampson, D., Sophokleous, S. and Muscat, R. (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl.) 93, 358-364.
  38. Wooltorton, J. R., Pidoplichko, V. I., Broide, R. S. and Dani, J. A. (2003) Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J. Neurosci. 23, 3176-3185. https://doi.org/10.1523/JNEUROSCI.23-08-03176.2003
  39. Yan, W. J., Tan, Y. C., Xu, J. C., Tang, X. P., Zhang, C., Zhang, P. B. and Ren, Z. Q. (2015) Protective effects of silibinin and its possible mechanism of action in mice exposed to chronic unpredictable mild stress. Biomol. Ther. (Seoul) 23, 245-250. https://doi.org/10.4062/biomolther.2014.138
  40. Zhong, P., Wang, W., Pan, B., Liu, X., Zhang, Z., Long, J. Z., Zhang, H. T., Cravatt, B. F. and Liu, Q. S. (2014) Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39, 1763-1776. https://doi.org/10.1038/npp.2014.24

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