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Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat

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Abstract

Rationale

Increasing experimental evidence suggests that impaired N-methyl-d-aspartic acid (NMDA) receptor (NMDAr) function could be a key pathophysiological determinant of schizophrenia. Agonists at the allosteric glycine (Gly) binding site of the NMDA complex can promote NMDAr activity, a strategy that could provide therapeutic efficacy for the disorder. NMDAr antagonists like phencyclidine (PCP) can induce psychotic and dissociative symptoms similar to those observed in schizophrenia and are therefore widely used experimentally to impair NMDA neurotransmission in vivo.

Objectives

In the present study, we used pharmacological magnetic resonance imaging (phMRI) to investigate the modulatory effects of endogenous and exogenous agonists at the NMDAr Gly site on the spatiotemporal patterns of brain activation induced by acute PCP challenge in the rat. The drugs investigated were d-serine, an endogenous agonist of the NMDAr Gly site, and SSR504734, a potent Gly transporter type 1 (GlyT-1) inhibitor that can potentiate NMDAr function by increasing synaptic levels of Gly.

Results

Acute administration of PCP induced robust and sustained activation of discrete cortico-limbo-thalamic circuits. Pretreatment with d-serine (1 g/kg) or SSR504734 (10 mg/kg) completely inhibited PCP-induced functional activation. This effect was accompanied by weak but sustained deactivation particularly in cortical areas.

Conclusions

These findings suggest that agents that stimulate NMDAr via Gly co-agonist site can potentiate NMDAr activity in the living brain and corroborate the potential for this class of drugs to provide selective enhancement of NMDAr neurotransmission in schizophrenia.

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References

  • Andersen JD, Pouzet B (2004) Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of d-serine. Neuropsychopharmacology 29:1080–1090

    Article  PubMed  CAS  Google Scholar 

  • Ballard TM, Pauly-Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E et al (2002) Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J Neurosci 22:6713–6723

    PubMed  CAS  Google Scholar 

  • Chen L, Muhlhauser M, Yang CR (2003) Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89:691–703

    Article  PubMed  CAS  Google Scholar 

  • Depoortere R, Dargazanli G, Estenne-Bouhtou G, Coste A, Lanneau C, Desvignes C et al (2005) Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology 30:1963–1985

    Article  PubMed  CAS  Google Scholar 

  • Friston KJ, Jezzard P, Turner R (1994) Analysis of functional MRI time-series. Hum Brain Mapp 1:153–171

    Article  Google Scholar 

  • Gozzi A, Schwarz AJ, Reese T, Bertani S, Crestan V, Bifone A (2005) Region-specific effects of nicotine on brain activity: a pharmacological MRI study in the drug-naïve rat. Neuropsychopharmacology 31:1690–1703

    Article  PubMed  CAS  Google Scholar 

  • Gozzi A, Ceolin L, Schwarz AJ, Reese T, Bertani S, Bifone A (2007) A multimodality investigation of cerebral haemodynamics and autoregulation in phMRI. Magn Reson Imaging 25:826–833

    Article  PubMed  Google Scholar 

  • Gozzi A, Schwarz AJ, Reese T, Crestan V, Bifone A (2008a) Drug-anaesthetic interaction in phMRI: the case of the pyschotomimetic agent phencyclidine. Magn Reson Imag. doi:10.1016/j.mri.2008.01.012

  • 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 33:1690–1703

    Article  PubMed  CAS  Google Scholar 

  • Greene R (2001) Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577

    Article  PubMed  CAS  Google Scholar 

  • Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW et al (1996) NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16:2034–2043

    PubMed  CAS  Google Scholar 

  • Harsing LG, Gacsalyi I, Szabo G, Schmidt E, Sziray N, Sebban C et al (2003) The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. Pharmacol Biochem Behav 74:811–825

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto A, Chiba Y (2004) Effect of systemic administration of -serine on the levels of - and -serine in several brain areas and periphery of rat. Eur J Pharmacol 495:153–158

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Fujita Y, Ishima T, Chaki S, Iyo M (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and d-serine. Eur Neuropsychopharmacol 18:414–421

    Article  PubMed  CAS  Google Scholar 

  • Hennig J, Nauerth A, Friedburg H (1986) RARE imaging: a fast imaging method for clinical MR. Magn Reson Med 3:823–833

    Article  PubMed  CAS  Google Scholar 

  • Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC (2007) Glutamate and Schizophrenia: Phencyclidine, N[hyphen (true graphic)]Methyl[hyphen (true graphic)]d[hyphen (true graphic)]Aspartate Receptors, and Dopamine-Glutamate Interactions. In: Anissa Abi[hyphen (true graphic) (ed). International Review of NeurobiologyIntegrating the Neurobiology of Schizophrenia. Academic, pp 69–108

  • Javitt DC, Heresco-Levy U (2000) Are glycine sites saturated in vivo? Arch Gen Psychiatry 57:1181–1183

    Article  PubMed  CAS  Google Scholar 

  • Jenkins BG, Chen Y-CI, Mandeville JB (2003) Pharmacological magnetic resonance imaging (phMRI). In: van Bruggen N, Roberts T (eds) Biomedical imaging in experimental neuroscience. CRC Press, New York, pp 155–209

    Google Scholar 

  • Karasawa Ji, Hashimoto K, Chaki S (2008) d-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 186:78–83

    Article  PubMed  CAS  Google Scholar 

  • Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, Figueroa DJ et al (2003) The glycine transporter type 1 inhibitor N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci 23:7586–7591

    PubMed  CAS  Google Scholar 

  • Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH (2007) NMDA receptors and schizophrenia. Curr Opin Pharmacol 7:48–55

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Anand A, Moghaddam B (2002) Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 59:663–664

    Article  PubMed  Google Scholar 

  • Large CH (2007) Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol 21:283–301

    Article  PubMed  CAS  Google Scholar 

  • Leeson PD, Iversen LL (1994) The glycine site on the NMDA receptor: structure–activity relationships and therapeutic potential. J Med Chem 37:4053–4067

    Article  PubMed  CAS  Google Scholar 

  • Li YH, Han TZ (2007) Glycine binding sites of presynaptic NMDA receptors may tonically regulate glutamate release in the rat visual cortex. J Neurophysiol 97:817–823

    Article  PubMed  CAS  Google Scholar 

  • Long KD, Mastropaolo J, Rosse RB, Deutsch SI (2007) Exogenously administered d-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice. Eur Neuropsychopharmacol 17:53–57

    Article  PubMed  CAS  Google Scholar 

  • MacDonald JF, Bartlett MC, Mody I, Pahapill P, Reynolds JN, Salter MW et al (1991) Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones. J Physiol 432:483–508

    PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D et al (1996) NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307

    Article  PubMed  CAS  Google Scholar 

  • Mandeville JB, Marota JJA, Kosofsky BE, Keltner JR, Weissleder R, Rosen B et al (1998) Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med 39:615–624

    Article  PubMed  CAS  Google Scholar 

  • Mandeville JB, Jenkins BG, Kosofsky BE, Moskowitz MA, Rosen B, Marota JJA (2001) Regional sensitivity and coupling of BOLD and CBV changes during stimulation of rat brain. Magn Reson Med 45:443–447

    Article  PubMed  CAS  Google Scholar 

  • Martina M, Krasteniakov NV, Bergeron R (2003) d-Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneurons. J Physiol 548:411–423

    Article  PubMed  CAS  Google Scholar 

  • Meur KL, Galante M, Angulo MC, Audinat E (2007) Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol 580:373–383

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ (2002) N-methyl-d-aspartate receptor-coupled glycineB receptors in the pathogenesis and treatment of schizophrenia: a critical review. Curr Drug Targets CNS Neurol Disord 1:191–213

    Article  PubMed  CAS  Google Scholar 

  • Nilsson M, Carlsson A, Carlsson ML (1997) Glycine and d-serine decrease MK-801-induced hyperactivity in mice. J Neural Transm 104:1195–1205

    Article  PubMed  CAS  Google Scholar 

  • Nishikawa T (2005) Metabolism and functional roles of endogenous d-serine in mammalian brains. Biol Pharm Bull 28:1561–1565

    Article  PubMed  CAS  Google Scholar 

  • Obrenovitch TP, Hardy AM, Urenjak J (1997) High extracellular glycine does not potentiate N-methyl-aspartate-evoked depolarization in vivo. Brain Res 746:190–194

    Article  PubMed  CAS  Google Scholar 

  • Panizzutti R, Rausch M, Zurbrugg S, Baumann D, Beckmann N, Rudin M (2005) The pharmacological stimulation of NMDA receptors via co-agonist site: an fMRI study in the rat brain. Neuroscience Letters 380:111–115

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotactic coordinates. Academic Press, San Diego

    Google Scholar 

  • Schwarz AJ, Reese T, Gozzi A, Bifone A (2003) Functional MRI using intravascular contrast agents: detrending of the relative cerebrovascular (rCBV) time course. Magn Reson Imaging 21:1191–1200

    Article  PubMed  CAS  Google Scholar 

  • Schwarz AJ, Zocchi A, Reese T, Gozzi A, Garzotti M, Varnier G et al (2004) Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration. Neuroimage 23:296–304

    Article  PubMed  CAS  Google Scholar 

  • Schwarz AJ, Danckaert A, Reese T, Gozzi A, Paxinos G, Watson C et al (2006a) A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI. NeuroImage 32:538–550

    Article  PubMed  Google Scholar 

  • Schwarz AJ, Whitcher B, Gozzi A, Reese T, Bifone A (2006b) Study-level wavelet cluster analysis and data-driven signal models in pharmacological MRI. J Neurosci Methods 159:346–360

    Article  PubMed  Google Scholar 

  • Sur C, Kinney GG (2007) Glycine transporter 1 inhibitors and modulation of NMDA receptor-mediated excitatory neurotransmission. Curr Drug Targets 8:643–649

    Article  PubMed  CAS  Google Scholar 

  • Tanii Y, Nishikawa T, Hashimoto A, Takahashi K (1994) Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat. J Pharmacol Exp Ther 269:1040–1048

    PubMed  CAS  Google Scholar 

  • Thomson AM (1990) Glycine is a coagonist at the NMDA receptor/channel complex. Prog Neurobiol 35:53–74

    Article  PubMed  CAS  Google Scholar 

  • Weissman AD, Dam M, London ED (1987) Alterations in local cerebral glucose utilization induced by phencyclidine. Brain Res 435:29–40

    Article  PubMed  CAS  Google Scholar 

  • Westergren I, Nystrom B, Hamberger A, Nordborg C, Johansson BB (1994) Concentrations of amino acids in extracellular fluid after opening of the blood–brain barrier by intracarotid infusion of protamine sulfate. J Neurochem 62:159–165

    Article  PubMed  CAS  Google Scholar 

  • Whitcher B, Schwarz AJ, Barjat H, Smart SC, Grundy RI, James MF (2005) Wavelet-based cluster analysis: data-driven grouping of voxel time courses with application to perfusion-weighted and MRI of the rat brain. Neuroimage 24:281–295

    Article  PubMed  Google Scholar 

  • Worsley KJ, Evans AC, Marrett S, Neelin P (1992) A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 12:900–918

    PubMed  CAS  Google Scholar 

  • Zafra F, Aragon C, Olivares L, Danbolt NC, Gimenez C, Storm-Mathisen J (1995) Glycine transporters are differentially expressed among CNS cells. J Neurosci 15:3952–3969

    PubMed  CAS  Google Scholar 

  • Zaharchuk G, Mandeville JB, Bogdanov Jr AA, Weissleder R, Rosen BR, Marota JJ (1999) Cerebrovascular dynamics of autoregulation and hypoperfusion. An MRI study of CBF and changes in total and microvascular cerebral blood volume during hemorrhagic hypotension. Stroke 30:2197–2204

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy

    Alessandro Gozzi, Hugh Herdon & Adam Schwarz

  2. Laboratory Animal Science, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy

    Simone Bertani, Valerio Crestan & Giuliano Turrini

  3. CPDM, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy

    Angelo Bifone

  4. Neuroimaging, GSK Neurosciences CEDD, Fleming 4, 37100, Verona, Italy

    Alessandro Gozzi

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  1. Alessandro Gozzi
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  2. Hugh Herdon
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  7. Angelo Bifone
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Correspondence to Alessandro Gozzi.

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Gozzi, A., Herdon, H., Schwarz, A. et al. Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat. Psychopharmacology 201, 273–284 (2008). https://doi.org/10.1007/s00213-008-1271-z

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  • DOI: https://doi.org/10.1007/s00213-008-1271-z

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