mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure
Tóm tắt
Depression is a prevalent neuropsychiatric disorder that affects an estimated 350 million people worldwide. Currently available treatments for depression are lacking in both speed of onset and efficacy. Recent pharmacological efforts have targeted the glutamatergic neurotransmitter system using the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine to produce rapid and robust antidepressant effects, however the widespread clinical use of ketamine is limited due to side effects and abuse liability. More recently, work evaluating metabotropic mGluR2/3 receptor antagonists has demonstrated many similarities with ketamine. Male, Sprague–Dawley rats were exposed to a chronic unpredictable stress paradigm, which produces decreased sucrose preference, a measure of anhedonia. Rats were then treated with vehicle or a single injection of the mGluR2/3 antagonist LY341495 (3 mg/kg, i.p.) and tested at 24 hrs, 48 hrs or 10 days after a single treatment. We demonstrate that a single treatment with LY341495 produces a rapid (within 1–2 days) and long-lasting (10 days) reversal of anhedonia caused by chronic unpredictable stress in rats. This model provides a rigorous test of rapid-acting agents as typical antidepressants require several weeks of treatment to produce a response. These data suggest that LY341495 has the ability to produce rapid and robust antidepressant effects similar to ketamine. Together, the results highlight the potential for similar compounds to produce rapid and lasting efficacy for the treatment of depression.
Tài liệu tham khảo
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS: The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003,289(23):3095–3105. 10.1001/jama.289.23.3095
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000,47(4):351–354. 10.1016/S0006-3223(99)00230-9
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK: A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006,63(8):856–864. 10.1001/archpsyc.63.8.856
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS: Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011,69(8):754–761. 10.1016/j.biopsych.2010.12.015
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010,329(5994):959–964. 10.1126/science.1190287
Neki A, Ohishi H, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N: Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody. Neurosci Lett 1996,202(3):197–200. 10.1016/0304-3940(95)12248-6
Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N: Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci 1997,17(19):7503–7522.
Ohishi H, Shigemoto R, Nakanishi S, Mizuno N: Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 1993,53(4):1009–1018. 10.1016/0306-4522(93)90485-X
Ohishi H, Shigemoto R, Nakanishi S, Mizuno N: Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 1993,335(2):252–266. 10.1002/cne.903350209
Marek GJ: Metabotropic glutamate2/3 (mGlu2/3) receptors, schizophrenia and cognition. Eur J Pharmacol 2010,639(1–3):81–90.
Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G: Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol 2008,592(1–3):96–102.
Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, Yoshimizu T, Yasuhara A, Sakagami K, Okuyama S, Nakanishi S, Nakazato A: MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology 2004,46(4):457–467. 10.1016/j.neuropharm.2003.10.009
Hascup ER, Hascup KN, Stephens M, Pomerleau F, Huettl P, Gratton A, Gerhardt GA: Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J Neurochem 2010,115(6):1608–1620. 10.1111/j.1471-4159.2010.07066.x
Moghaddam B, Adams B, Verma A, Daly D: Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997,17(8):2921–2927.
Karasawa J, Shimazaki T, Kawashima N, Chaki S: AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 2005,1042(1):92–98. 10.1016/j.brainres.2005.02.032
Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK: Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008,63(4):349–352. 10.1016/j.biopsych.2007.05.028
Dwyer JM, Lepack AE, Duman RS: mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol 2012,15(4):429–434. 10.1017/S1461145711001702
Koike H, Iijima M, Chaki S: Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists. Neuropharmacology 2011,61(8):1419–1423. 10.1016/j.neuropharm.2011.08.034
Papp M, Moryl E, Willner P: Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol 1996,296(2):129–136. 10.1016/0014-2999(95)00697-4
Ornstein PL, Bleisch TJ, Arnold MB, Kennedy JH, Wright RA, Johnson BG, Tizzano JP, Helton DR, Kallman MJ, Schoepp DD, Herin M: 2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. J Med Chem 1998,41(3):358–378. 10.1021/jm970498o