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Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI

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Abstract

Background

An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.

Methods

Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.

Results

Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.

Conclusion

Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.

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References

  • Areosa SA, Sherriff F, McShane R (2005): Memantine for dementia. The cochrane database for systematic reviews. CD 003154.pub3. 2005

  • Ashburner J, Neelin P, Collins DL, Evans A, Friston K (1997) Incorporating prior knowledge into image registration. NeuroImage 6:344–352

    Article  PubMed  CAS  Google Scholar 

  • Alley GM, Bailey JA, Chen D, Ray B, Puli LK, Tanila H, Banerjee PK, Lahiri DK (2010) Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J Neurosci Res 88(1):143–154

    Google Scholar 

  • Bifone A, Gozzi A, Schwarz AJ (2010) Functional connectivity in the rat brain: a complex network approach. Magn Reson Imaging 28(8):1200–1209, Review

    Article  PubMed  Google Scholar 

  • Borsook D, Becerra L (2010) Using NMR approaches to drive the search for new CNS therapeutics. Curr Opin Investig Drugs 11(7):771–778, Review

    PubMed  CAS  Google Scholar 

  • Borsook D, Becerra L, Hargreaves R (2006) A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov 5:411–424

    Article  PubMed  CAS  Google Scholar 

  • Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C (2008) Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 32(5):1014–1023, Review

    Article  PubMed  Google Scholar 

  • Chin CL, Upadhyay J, Marek GJ, Baker SJ, Zhang M, Mezler M, Fox GB, Day M (2011) Awake rat pharmacological magnetic resonance imaging as a translational pharmacodynamic biomarker: metabotropic glutamate 2/3 agonist modulation of ketamine-induced blood oxygenation level dependence signals. J Pharmacol Exp Ther 336(3):709–715

    Article  PubMed  CAS  Google Scholar 

  • Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ (2003) Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 28(2):265–275

    Article  PubMed  CAS  Google Scholar 

  • Coyle JT, Tsai G (2004) NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia. Int Rev Neurobiol 59:491–515, Review

    Article  PubMed  CAS  Google Scholar 

  • Danysz W, Parsons CG, Mobius HJ, Stoffler A, Quack G (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer’s disease—a unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2(2–3):85–97

    Article  PubMed  CAS  Google Scholar 

  • Dawson N, Thompson RJ, McVie A, Thomson DM, Morris BJ, Pratt JA (2010) Modafinil reverses phencyclidine-induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity. Schizophr Bull 38(3):457–474

    Article  PubMed  Google Scholar 

  • Dedeurwaerdere S, Wintmolders C, Straetemans R, Pemberton D, Langlois X (2011) Memantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds: exemplified by activity of an mGlu2/3 receptor agonist. Psychopharmacology 214:505–514

    Article  PubMed  CAS  Google Scholar 

  • Delgado y Palacios R, Campo A, Henningsen K, Verhoye M, Poot D, Dijkstra J, Van Audekerke J, Benveniste H, Sijbers J, Wiborg O, Van der Linden A (2011) Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol Psychiatry 70(5):449–457

    Article  PubMed  Google Scholar 

  • Ford JM, Mathalon DH, Whitfield S, Faustman WO, Roth WT (2002) Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol Psychiatry 51(6):485–492

    Article  PubMed  Google Scholar 

  • Fox GB, Chin CL, Luo F, Day M, Cox BF (2009) Translational neuroimaging of the CNS: novel pathways to drug development. Mol Interv 9:302–313

    Article  PubMed  CAS  Google Scholar 

  • Gilmour G, Pioli EY, Dix SL, Smith JW, Conway MW, Jones WT, Loomis S, Mason R, Shahabi S, Tricklebank MD (2009) Diverse and often opposite behavioral effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia. Psychopharmacology 205:203–216

    Article  PubMed  CAS  Google Scholar 

  • Gozzi A, Herdon H, Schwarz A, Bertani S, Crestan V, Turrini G, Bifone A (2008a) Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat. Psychopharmacol (Berl) 201(2):273–284

    Article  CAS  Google Scholar 

  • Gozzi A, Large CH, Schwarz A, Bertani S, Crestan V, Bifone A (2008b) Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33(7):1690–1703

    Article  PubMed  CAS  Google Scholar 

  • Hackler EA, Byun NE, Jones CK, Williams JM, Baheza R, Sengupta S, Grier MD, Avison M, Conn PJ, Gore JC (2010) Selective potentiation of the metabotropic glutamate receptor subtype 2 blocks phencyclidine-induced hyperlocomotion and brain activation. Neuroscience 168(1):209–218

    Article  PubMed  CAS  Google Scholar 

  • Hlustik P, Noll DC, Small SL (1998) Suppression of vascular artifacts in functional magnetic resonance images using MR angiograms. NeuroImage 7:224–231

    Article  PubMed  CAS  Google Scholar 

  • Houston GC, Papadakis NG, Carpenter TA, Hall LD, Mukherjee B, James MF, Huang CL (2001) Mapping of brain activation in response to pharmacological agents using fMRI in the rat. Magn Reson Imaging 19(7):905–919

    Article  PubMed  CAS  Google Scholar 

  • Jensen JH, Helpern JA, Ramani A, Lu H, Kaczynski K (2005) Diffusional kurtosis imaging: the quantification of non-Gaussian water diffusion by means of magnetic resonance imaging. Magn Reson Med 53(6):1432–1440

    Article  PubMed  Google Scholar 

  • Jonckers E, Van Audekerke J, De Visscher G, Van der Linden A, Verhoye M (2011) Functional connectivity fMRI of the rodent brain: comparison of functional connectivity networks in rat and mouse. PLoS One 6(4):e18876

    Article  PubMed  CAS  Google Scholar 

  • Kalthoff D, Seehafer JU, Po C, Wiedermann D, Hoehn M (2011) Functional connectivity in the rat at 11.7T: impact of physiological noise in resting state fMRI. NeuroImage 54(4):2828–2839

    Article  PubMed  Google Scholar 

  • Kastrup A, Baudewig J, Schnaudigel S, Huonker R, Becker L, Sohns JM, Dechent P, Klingner C, Witte OW (2008) Behavioral correlates of negative BOLD signal changes in the primary somatosensory cortex. NeuroImage 41(4):1364–1371

    Article  PubMed  Google Scholar 

  • King JA, Garelick TS, Brevard ME, Chen W, Messenger TL, Duong TQ, Ferris CF (2005) Procedure for minimizing stress for fMRI studies in conscious rats. J Neurosci Methods 148:154–160

    Google Scholar 

  • Krienen FM, Buckner RL (2009) Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cereb Cortex 19(10):2485–2497

    Article  PubMed  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    Article  PubMed  CAS  Google Scholar 

  • Kyriakopoulos M, Frangou S (2009) Recent diffusion tensor imaging findings in early stages of schizophrenia. Curr Opin Psychiatry 22:168–176

    Article  PubMed  Google Scholar 

  • Langsjo JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, Sipilä H, Kurki T, Silvanto M, Scheinin H (2003) Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 99(3):614–623

    Article  PubMed  Google Scholar 

  • Langsjo JW, Salmi E, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Viljanen T, Kurki T, Silvanto M, Scheinin H (2004) Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans. Anesthesiology 100(5):1065–1071

    Article  PubMed  Google Scholar 

  • Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC (2002) Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 51(12):1008–1011

    Article  PubMed  Google Scholar 

  • Leemans A, Jones DK (2009) The B-matrix must be rotated when correcting for subject motion in DTI data. Magn Reson Med 61(6):1336–1349

    Article  PubMed  Google Scholar 

  • Ling Z, King JA, Zhang N (2011) Uncovering intrinsic connectional architecture of functional networks in awake rat brain. J Neurosci 31(10):3776–3783

    Article  Google Scholar 

  • Littlewood CL, Jones N, O'Neill MJ, Mitchell SN, Tricklebank M, Williams SC (2006a) Mapping the central effects of ketamine in the rat using pharmacological MRI. Psychopharmacol (Berl) 186(1):64–81

    Article  CAS  Google Scholar 

  • Littlewood CL, Cash D, Dixon AL, Dix SL, White CT, O'Neill MJ, Tricklebank M, Williams SC (2006b) Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat. NeuroImage 32(4):1733–1746

    Article  PubMed  Google Scholar 

  • Lowe AS, Barker GJ, Beech JS, Ireland MD, Williams SC (2008) A method for removing global effects in small-animal functional MRI. NMR Biomed 21:53–58

    Article  PubMed  Google Scholar 

  • Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16(2):187–198

    Article  PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    Article  PubMed  CAS  Google Scholar 

  • Mechri A, Micallef J, Blin O, Saoud M, Daléry J, Gaha L (2001a) Pharmacological modulation of the effects induced by ketamine at subanesthetic doses. Therapie 56(5):617–622, Review

    PubMed  CAS  Google Scholar 

  • Mechri A, Saoud M, Khiari G, d’Amato T, Dalery J, Gaha L (2001b) Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine. Encephale 27(1):53–59, Review

    PubMed  CAS  Google Scholar 

  • Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF (2005) Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 62(4):379–386

    Article  PubMed  Google Scholar 

  • Nagai T, Noda Y, Une T, Furukawa K et al (2003) Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice. Neuroreport 14:269–272

    Article  PubMed  CAS  Google Scholar 

  • Olney JW, Farber NB (1995) NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 13:335–345

    Article  PubMed  CAS  Google Scholar 

  • Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254:1515–1518

    Article  PubMed  CAS  Google Scholar 

  • Parsons CG, Stoffler A, Danysz W (2007) Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Neuropharmacology 53:699–723

    Article  PubMed  CAS  Google Scholar 

  • Pawela CP, Biswal BB, Hudetz AG, Schulte ML, Li R, Cho YR, Matloub HS, Hyde JS (2009) A protocol for use of medetomidine anesthesia in rats for extended studies using task-induced BOLD contrast and resting-state functional connectivity. NeuroImage 46:1137–1147

    Article  PubMed  Google Scholar 

  • Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S (2006) Memantine treatment in mild to moderate alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 14(8):704–715

    Article  PubMed  Google Scholar 

  • Schridde U, Khubchandani M, Motelow JE, Sanganahalli BG, Hyder F, Blumenfeld H (2008) Negative BOLD with large increases in neuronal activity. Cerebr Cortex 18(8):1814–1827

    Article  Google Scholar 

  • Schwarz AJ, Gozzi A, Reese T, Heidbreder CA, Bifone A (2007) Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D3 receptor antagonist SB277011A. Magn Reson Imaging 25(6):811–820

    Article  PubMed  CAS  Google Scholar 

  • Sekar S, Raley JM, Lowe AS, Sharp T, Sibson NR, Blamire AM, Steckler T, Shoaib M (2010) Mapping of anxiogenic neuronal profiles induced by the GABA inverse agonist FG-7142 and caffeine using pharmacological magnetic resonance imaging. Eur Neuropsychopharmacol 20(1):S23

    Article  Google Scholar 

  • Sekar S, Verhoye M, Van Audekerke J, Vanhoutte G, Lowe AS, Blamire AM, Steckler T, Van der Linden A, Shoaib M (2011a) Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging. Psychopharmacol (Berl) 213:521–531

    Article  CAS  Google Scholar 

  • Sekar S, Van Audekerke J, Vanhoutte G, Lowe AS, Blamire AM, Van der Linden A, Steckler T, Shoaib M, Verhoye M (2011b) Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging. Psychopharmacol (Berl) 217(4):549–557

    Article  CAS  Google Scholar 

  • Sigurdsson T, Stark KL, Karayiorgou M, Gogos JA, Gordon JA (2010) Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464(7289):763–767

    Article  PubMed  CAS  Google Scholar 

  • Tamminga CA (2006) The neurobiology of cognition in schizophrenia. J Clin Psychiatry 67(Suppl 9):9–13, discussion 36-42

    PubMed  CAS  Google Scholar 

  • Van Hecke W, Sijbers J, D'Agostino E, Maes F, De Backer S, Vandervliet E, Parizel PM, Leemans A (2008) On the construction of an inter-subject diffusion tensor magnetic resonance atlas of the healthy human brain. NeuroImage 43(1):69–80

    Article  PubMed  Google Scholar 

  • Ver Donck L, Duytschaever H, Willems R (2011): Low dose subchronic phencyclidine (PCP) pretreatment potentiates acute PCP-induced hyperlocomotion in adult rats: a model of schizophrenia? Society for Neuroscience, abstract 368.13.

  • Veraart J, Poot DH, Van Hecke W, Blockx I, Van der Linden A, Verhoye M, Sijbers J (2011) More accurate estimation of diffusion tensor parameters using diffusion Kurtosis imaging. Magn Reson Med 65(1):138–145

    Article  PubMed  Google Scholar 

  • Weber R, Ramos-Cabrer P, Wiedermann D, van Camp N, Hoehn M (2006) A fully noninvasive and robust experimental protocol for longitudinal fMRI studies in the rat. NeuroImage 29:1303–1310

    Article  PubMed  Google Scholar 

  • White T, Kendi AT, Lehericy S, Kendi M, Karatekin C, Guimaraes A, Davenport N, Schulz SC, Lim KO (2007) Disruption of hippocampal connectivity in children and adolescents with schizophrenia—a voxel-based diffusion tensor imaging study. Schizophr Res 90:302–307

    Article  PubMed  Google Scholar 

  • Wilcock G, Mobius HJ, Stoffler A (2002) A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia. Int Clin Pychopharmacol 17:297–305

    Article  CAS  Google Scholar 

  • Williams KA, Magnuson M, Majeed W, Laconte SM, Peltier SJ, Keilholz SD (2010) Comparison of alpha-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat. Magn Reson Imaging 28:995–1003

    Article  PubMed  CAS  Google Scholar 

  • Williamson PC, Allman JM (2012) A framework for interpreting functional networks in schizophrenia. Front Hum Neurosci 6:184

    Article  PubMed  Google Scholar 

  • Winblad B, Jones RW, Wirth Y, Stöffler A, Möbius HJ (2007) Memantine in Moderate to Severe Alzheimer´s Disease: A Meta-Analysis of Randomised Clinical Trials. Dement Geriatr Cogn Disord 24:20–27

    Article  PubMed  CAS  Google Scholar 

  • Wong DF, Tauscher J, Grunder G (2009) The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacology 34:187–203

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Li Q, Wang D, Shi L, Lu G, Sun L, Wang L, Zhu W, Mak YT, Wong N, Wang Y, Pan F, Yew DT (2011) Mapping the central effects of Chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI). Neurotoxicology 33(1):70–77

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful for the financial support of Janssen Research & Development, Beerse, Belgium (Postdoctoral fellowship of Dr. Sekar). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F2-2011-278850 (INMiND). Prof. Van der Linden and Prof. Dedeurwaerdere received funds from Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO) (G.0586.12). Contributions of Mrs. Hilde Duytschaever, Mr. Patrick De Haes and Mr. Michel Mahieu, Mrs. Sofie Embrechts and Mrs. Liesbeth Mertens from Neuroscience Discovery, Janssen Research and Development for their support with the subchronic treatments and in generating the locomotor activity data are acknowledged. Results from this multimodal imaging study have been presented in part as abstracts at conferences including FlandersBio (2011), CINP Pacific Asia meet (2011), EMIM (2011) and WMIC (2011).

Conflict of interest

The authors declare no conflict of interest.

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Author notes

  1. S. Sekar

    Present address: SBIC, A*Star, Biopolis, Singapore

Authors and Affiliations

  1. Bio-Imaging Lab, Department of Biomedical Sciences, University of Antwerp, Campus Drie Eiken, D.UC.109, Universiteitsplein 1, 2610, Wilrijk, Belgium

    S. Sekar, E. Jonckers, M. Verhoye, J. Van Audekerke & A. Van der Linden

  2. Neuroscience Discovery, Janssen Research and Development, Beerse, Belgium

    S. Sekar, R. Willems, L. Ver Donck & T. Steckler

  3. Vision Lab, University of Antwerp, Antwerp, Belgium

    J. Veraart & J. Sijbers

  4. Theoretical Neurobiology, University of Antwerp, Antwerp, Belgium

    J. Couto & M. Giugliano

  5. ADME/Tox, Janssen Research and Development, Beerse, Belgium

    K. Wuyts & C. Mackie

  6. Translational Neuroscience, University of Antwerp, Antwerp, Belgium

    S. Dedeurwaerdere

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  1. S. Sekar
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Sekar, S., Jonckers, E., Verhoye, M. et al. Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI. Psychopharmacology 227, 479–491 (2013). https://doi.org/10.1007/s00213-013-2966-3

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