Behavioral and Brain Functions | |
Differential effects of diazepam and MPEP on habituation and neuro-behavioural processes in inbred mice | |
Amber R Salomons3  Nathaly Espitia Pinzon4  Hetty Boleij3  Susanne Kirchhoff3  Saskia S Arndt3  Rebecca E Nordquist2  Lothar Lindemann1  Georg Jaeschke1  Will Spooren1  Frauke Ohl3  | |
[1] F. Hoffmann-La Roche Ltd. Pharmaceuticals Division, Discovery Neuroscience, Basel, Switzerland | |
[2] Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, Utrecht, CL, 3584, The Netherlands | |
[3] Rudolf Magnus Institute of Neuroscience, Universiteitsweg 100, Utrecht, CG, 3584, The Netherlands | |
[4] Department of Animals in Science and Society, Division of Animal Welfare and Laboratory Animal Science, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584, Utrecht, CM, The Netherlands | |
关键词: mGluR5 antagonist; Cortisosterone; C-Fos; Benzodiazepines; Behavior; Anxiety; | |
Others : 797508 DOI : 10.1186/1744-9081-8-30 |
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received in 2011-11-07, accepted in 2012-06-11, 发布年份 2012 | |
【 摘 要 】
Background
Previous studies have demonstrated a profound lack of habituation in 129P3 mice compared to the habituating, but initially more anxious, BALB/c mice. The present study investigated whether this non-adaptive phenotype of 129P3 mice is primarily based on anxiety-related characteristics.
Methods
To test this hypothesis and extend our knowledge on the behavioural profile of 129P3 mice, the effects of the anxiolyticdiazepam (1, 3 and 5 mg/kg) and the putative anxiolytic metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 3, 10 and 30 mg/kg) treatment on within-trial (intrasession) habituation, object recognition (diazepam: 1 mg/kg; MPEP 10 mg/kg) and on the central-nervous expression of the immediate early gene c-Fos (diazepam: 1 mg/kg; MPEP 10 mg/kg) were investigated.
Results
Behavioural findings validated the initially high, but habituating phenotype of BALB/c mice, while 129P3 mice were characterized by impaired intrasession habituation. Diazepam had an anxiolytic effect in BALB/c mice, while in higher doses caused behavioural inactivity in 129P3 mice. MPEP revealed almost no anxiolytic effects on behaviour in both strains, but reduced stress-induced corticosterone responses only in 129P3 mice. These results were complemented by reduced expression of c-Fos after MPEP treatment in brain areas related to emotional processes, and increased c-Fos expression in higher integrating brain areas such as the prelimbic cortex compared to vehicle-treated 129P3 mice.
Conclusions
These results suggest that the strain differences observed in (non)adaptive anxiety behaviour are at least in part mediated by differences in gamma-aminobutyric acid- A and mGluR5 mediated transmission.
【 授权许可】
2012 Salomons et al.; licensee BioMed Central Ltd.
【 预 览 】
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【 参考文献 】
- [1]Ohl F, Arndt SS, van der Staay FJ: Pathological anxiety in animals. Vet J 2008, 175:18-26.
- [2]Salomons AR, van Luijk JA, Reinders NR, Kirchhoff S, Arndt SS, Ohl F: Identifying emotional adaptation: behavioural habituation to novelty and immediate early gene expression in two inbred mouse strains. Genes Brain Behav 2010, 9:1-10.
- [3]McNaughton N: Cognitive dysfunction resulting from hippocampal hyperactivity–a possible cause of anxiety disorder? Pharmacol Biochem Behav 1997, 56:603-611.
- [4]Belzung C, Berton F: Further pharmacological validation of the BALB/c neophobia in the free exploratory paradigm as an animal model of trait anxiety. Behav Pharmacol 1997, 8:541-548.
- [5]Belzung C, Griebel G: Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 2001, 125:141-149.
- [6]Salomons AR, Kortleve T, Reinders NR, Kirchhoff S, Arndt SS, Ohl F: Susceptibility of a potential animal model for pathological anxiety to chronic mild stress. Behav Brain Res 2010, 209:241-248.
- [7]Rodgers RJ, Boullier E, Chatzimichalaki P, Cooper GD, Shorten A: Contrasting phenotypes of C57BL/6JOlaHsd, 129 S2/SvHsd and 129/SvEv mice in two exploration-based tests of anxiety-related behaviour. Physiol Behav 2002, 77:301-310.
- [8]Tang X, Sanford LD: Home cage activity and activity-based measures of anxiety in 129P3/J, 129X1/SvJ and C57BL/6 J mice. Physiol Behav 2005, 84:105-115.
- [9]Belzung C, LePape G: Comparison of different behaviorbehavioural test situations used in psychopharmacology for measurement of anxiety. Physiol Behav 2002, 566:23-628.
- [10]Ohl F: Animal models of anxiety. Handb Exp Pharmacol 2005, 35-69.
- [11]Dere E, de Souza Silva MA, Topic B, Fiorillo C, Li JS, Sadile A: Aged endothelial nitric oxide synthase knockout mice exhibit higher mortality concomitant with impaired open-field habituation and alterations in forebrain neurotransmitter levels. Genes Brain Behav 2002, 1:204-213.
- [12]Leussis MP, Bolivar VJ: Habituation in rodents: A review of behavior, neurobiology, and genetics. Neurosci Biobehav Rev 2006, 30:1045-1064.
- [13]Faravelli C, Rosi S, Truglia E: Treatments. In Benzodiazepines. Edited by Nutt DJ, Ballenger JC. Blackwell Science, Oxford; 2003:315-338.
- [14]Shader RI, Greenblatt DJ: Use of benzodiazepines in anxiety disorders. N Engl J Med 1993, 328:1398-1405.
- [15]Fernandes C, Arnot MI, Irvine EE, Bateson AN, Martin IL, File SE: The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam. Psychopharmacology 1999, 145:251-259.
- [16]Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1993, 38:1493-1503.
- [17]Nordquist RE, Durkin S, Jaeschke G, Spooren W: Stress-induced hyperthermia: effects of acute and repeated dosing of MPEP. Eur J Pharmacol 2007, 568:199-202.
- [18]Spooren WP, Vassout A, Neijt HC, Kuhn R, Gasparini F, Roux S: Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther 2000, 295:1267-1275.
- [19]Spooren WP, Gasparini F, Salt TE, Kuhn R: Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. Trends Pharmacol Sci 2001, 22:331-337.
- [20]Piechaczyk M, Blanchard JM: c-fos proto-oncogene regulation and function. Crit Rev Oncology/Hematology 1994, 17:93-131.
- [21]Chan RKW, Brown ER, Ericsson A, Kovacs KJ, Sawchenko PE: Comparison of Two Immediate-Early Genes, c-fos and NGFI-B, as Markers for Functional Activation in Stress-related Neuroendocrine Circuitry. J of Neuroscience 1993, 13:5126-5138.
- [22]Ohl F, Sillaber I, Binder E, Keck ME, Holsboer F: Differential analysis of behavior and diazepam-induced alterations in C57BL/6 N and BALB/c mice using the modified hole board test. J Psychiatr Res 2001, 35:147-154.
- [23]Arzt E, Holsboer F: CRF signaling: molecular specificity for drug targeting in the CNS. Trends Pharmacol Sci 2006, 27:531-538.
- [24]Muigg P, Hoelzl U, Palfrader K, Neumann I, Wigger A, Landgraf R: Altered Brain Activation Pattern Associated With Drug-Induced Attenuation of Enhanced Depression-Like Behavior in Rats Bred for High Anxiety. Biol Psychiatry 2007, 61:782-796.
- [25]Nguyen NK, Keck ME, Hetzenauer A, Thoeringer CK, Wurst W, Deussing JM: Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge. Psychopharmacology (Berl) 2006, 188:374-385.
- [26]Franklin KGB, Paxinos G: The mouse brain in stereotaxic coordinates. Academic 1997. Press
- [27]Field A: Discovering statistics using SPSS. 3rd edition. SAGE Publications Ltd, London; 2009.
- [28]Conover WJ, Iman RL: Analysis of covariance using the rank transformation. Biometrics 1982, 38:715-724.
- [29]Algina J, Kesselman HJ: Detecting repeated measures effects with univariate and multivariate statistics. Psychological Methods 1997, 2:208-218.
- [30]Rodgers RJ, Davies B, Shore R: Absence of anxiolytic response to chlordiazepoxide in two common background strains exposed to the elevated plus-maze: importance and implications of behavioural baseline. Genes Brain Behav 2002, 1:242-251.
- [31]Griebel G, Belzung C, Misslin R, Vogel E: The free-exploratory paradigm: an effective method for measuring neophobic behaviour in mice and testing potential neophobia-reducing drugs. Behav Pharmacol 1993, 4:637-644.
- [32]Griebel G, Belzung C, Perrault G, Sanger DJ: Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology (Berl) 2000, 148:164-170.
- [33]Robertson HA: Benzodiazepine receptors in "emotional" and "non-emotional" mice; comparison of four strains. Eur J Pharmacol 1979, 56:163-166.
- [34]Mikkelsen JD, Soderman A, Kiss A, Mirza N: Effects of benzodiazepines receptor agonists on the hypothalamic-pituitary-adrenocortical axis. Eur J Pharmacol 2005, 519:223-230.
- [35]Makowska IJ, Weary DM: Rat aversion to induction with inhalant anaesthetics. Applied Animal Behaviour Science 2009, 119:229-235.
- [36]Bogeart MJ, Groenink L, Oosting RS, Westphal KG, van der Gugten J, Olivier B: Mouse strain differences in autonomic responses. Genes Brain Behav 2006, 5:139-149.
- [37]Ballard TM, Woolley ML, Prinssen E, Huwyler J, Porter R, Spooren W: The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison. Psychopharmacology (Berl) 2005, 179:218-229.
- [38]Rodgers RJ, Coa BJ, Dalvi A, Holmes A: Animal models of anxiety: an ethological perspective. Braz J Med Biol Res 1997, 30:289-304.
- [39]Ohl F, Holsboer F, Landgraf R: The modified hole board as differential screen for behaviour in rodents. Behav Res Methods Instrum Comput 2001, 33:392-397.
- [40]Blanchard DC, Griebel G, Blanchard RJ: Mouse defense behaviors: pharmacological and behavioral assays for anxiety and panic. Neurosc. Biobeh Rev 2001, 25:205-218.
- [41]Goldman-Rakic PS: Architecture of the prefrontal cortex and the central executive. Ann N Y Acad Sci 1995, 769:71-83.
- [42]Herman JP, Ostrander MM, Mueller NK, Figueiredo H: Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 2005, 29:1201-1213.
- [43]Makino S, Hashimoto K, Gold PW: Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav 2002, 73:147-158.
- [44]Sheehan TP, Chambers RA, Russell DS: Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res Brain Res Rev 2004, 46:71-117.
- [45]McNaughton N, Corr PJ: A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci Biobehav Rev 2004, 28:285-305.
- [46]Singewald N, Salchner P, Sharp T: Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry 2003, 53:275-283.
- [47]George SA, Hutson PH, Stephens DN: Differential effects of MPEP and diazepam in tests of conditioned emotional response and Pavlovian-to-instrumental transfer suggests 'anxiolytic' effects are mediated by different mechanisms. Psychopharmacology (Berl) 2009, 204:499-509.
- [48]Romano C, Sesma MA, McDonald CT, O'Malley K, van den Pol AN, Olney JW: Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 1995, 355:455-469.
- [49]Shigemoto R, Nomura S, Ohishi H, Sugihara H, Nakanishi S, Mizuno N: Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett 1993, 163:53-57.
- [50]Benquet P, Gee CE, Gerber U: Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes. J Neurosci 2002, 22:9679-9686.
- [51]Gerber U, Gee CE, Benquet P: Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 2007, 7:56-61.
- [52]Pintor A, Pezzola A, Reggio R, Quarta D, Popoli P: The mGlu5 receptor agonist CHPG stimulates striatal glutamate release: possible involvement of A2A receptors. Neuroreport 2000, 11:3611-3614.
- [53]Kemp JA, McKernan RM: NMDA receptor pathways as drug targets. Nat Neurosci 2002, 5:1039-1042. Suppl
- [54]Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW: Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci U S A 1993, 90:6591-6595.
- [55]Simon AB, Gorman JM: Advances in the treatment of anxiety: targeting glutamate. NeuroRx 2003, 3:57-68.
- [56]Thomas LS, Jane DE, Gasparini F, Croucher MJ: Glutamate release inhibiting properties of the novel mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP): complementary in vitro and in vivo evidence. Neuropharmacology 2001, 41:523-527.
- [57]Camp M, Norcross M, Whittle N, Feyder M, D'Hanis W, Yilmazer-Hanke D: Impaired Pavlovian fear extinction is a common phenotype across genetic lineages of the 129 inbred mouse strain. Genes Brain Behav 2009, 8:744-752.
- [58]Quirk GJ, Garcia R, Gonzalez-Lima F: Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 2006, 60:337-343.
- [59]Davidson RJ: Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 2002, 51:68-80.
- [60]Beuzen A, Belzung C: Link between emotional memory and anxiety states: a study by principal component analysis. Physiol Behav 1995, 58:111-118.
- [61]Kuribara H, Asahi T: Assessment of the anxiolytic and amnesic effects of three benzodiazepines, diazepam, alprazolam and triazolam, by conflict and non-matching to sample tests in mice. Nihon Shinkei Seishin Yakurigaku Zasshi 1997, 17:1-6.
- [62]Tomaz C, Dickinson-Anson H, McGaugh JL: Basolateral amygdala lesions block diazepam-induced anterograde amnesia in an inhibitory avoidance task. PNAS USA 1992, 89:3615-3619.
- [63]Barker GR, Bashir ZI, Brown MW, Warburton EC: A temporally distinct role for group I and group II metabotropic glutamate receptors in object recognition memory. Learn Mem 2006, 13:178-186.
- [64]Christoffersen GR, Simonyi A, Schachtman TR, Clausen B, Clement D, Bjerre VK: MGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats. Behav Brain Res 2008, 191:235-245.
- [65]Bouwknecht JA, Paylor R: Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav Brain Res 2002, 136:489-501.
- [66]Cryan JF, Holmes A: The ascent of mouse: advances in modelling human depression and anxiety. Nature Reviews 2005, 4:775-789.