Abstract
Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.
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Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biol Psychiatry 43:811–816
Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649
Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, Hichwa RD (1997) Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349:1730–1734
Attucci S, Albani-Torregrossa S, Moroni F, Pellegrini-Giampietro DE (2001) Metabotropic glutamate receptors stimulate phospholipase D via different pathways in the adult and neonate rat hippocampus. Neurochem Res 26:1151–1155
Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 20:7871–7879
Battaglia G, Monn JA, Schoepp DD (1997) In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats. Neurosci Lett 229:161–164
Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP (1992) Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 12:924–929
Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. Journal of Neurochemistry 75:889–907
Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170
Clinton SM, Haroutunian V, Davis KL, Meador-Woodruff JH (2003) Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am J Psychiatry 160:1100–1109
Conn JP, Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237
Coyle JT, Tsai G, Goff DC (2002) Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr Drug Target CNS Neurol Disord 1:183–189
Crawford J, Curtis D (1964) The excitation and depression of mammalian cortical neurons by amino acids. Br J Pharmacol 23:323–329
Curtis D, Phillis J, Watkins J (1960) The chemical excitation of spinal neurons by certain acidic amino acids. J Physiol 150:656–682
De Blasi A, Conn PJ, Pin J, Nicoletti F (2001) Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci 22:114–120
Doherty AJ, Palmer MJ, Henley JM, Collingridge GL, Jane DE (1997) (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36:265–267
Goldman-Rakic P (1994) Cerebral cortical mechanisms in schizophrenia. Neuropsychopharmacology 10:22S–27S
Greene R (2001) Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577
Gur RE, Cowell PE, Latshaw A, Turetsky BI, Grossman RI, Arnold SE, Bilker WB, Gur RC (2000) Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Arch Gen Psychiatry 57:761–768
Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122:593–624
Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications [comment]. Lancet 361:417–419
Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A (2002) The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 43:1199–1209
Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108
Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B (2004) Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology (in press)
Huntley G, Vickers J, Morrison J (1994) Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: organizational features related to cortical circuitry, function and disease. Trends Neurosci 17:536–543
Javitt DC (2002) Glycine modulators in schizophrenia. Curr Opin Invest Drugs 3:1067–1072
Johnson MP, Baez M, Jagdmann GE, Jr., Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD (2003) Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J Med Chem 46:3189–3192
Kinney G, Wittmann M, Bristow L, Campbell U, Conn P (2002) Behavioral consequences of mGluR5 and NMDA receptor antagonist interaction: implications for schizophrenia. Neuropharmacology 43:292
Kinney G, Burno M, Campbell U, Hernandez L, Rodriguez D, Bristow L, Conn P (2003) Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 306:116–123
Knoflach F, Mutel V, Jolidon S, Kew JN, Malherbe P, Vieira E, Wichmann J, Kemp JA (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site.[erratum appears in Proc Natl Acad Sci USA 2001 Dec 18;98(26):15393]. Proc Natl Acad Sci USA 98:13402–13407
Konradi C, Heckers S (2003) Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 97:153–179
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers Jr M, 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
Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, D’Souza DC, Lipschitz D, Abi-Dargham A, Charney DS (2000) Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry 47:137–143
Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 169:215–233
Lewis DA, Anderson SA (1995) The functional architecture of the prefrontal cortex and schizophrenia. Psychol Med 25:887–894
Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706
Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci 21:5925–5934
Marino MJ, Conn PJ (2002) Direct and indirect modulation of the N-methyl d-aspartate receptor. Curr Drug Target CNS Neurol Disord 1:1–16
Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. Proc Natl Acad Sci USA 100:13668–13673
McCullumsmith RE, Meador-Woodruff JH (2002) Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26:368–375
Moghaddam B (2003) Bringing order to the glutamate chaos in schizophrenia. Neuron 40:881–884
Moghaddam B, Adams B (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352
Moghaddam B, Adams B, Verma A, Daly D (1997) 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 17:2921–2927
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118
Nicoletti F, Meek JL, Iadarola MJ, Chuang DM, Roth BL, Costa E (1986) Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J Neurochem 46:40–46
O’Brien JA, Lemaire W, Chen TB, Chang RS, Jacobson MA, Ha SN, Lindsley CW, Schaffhauser HJ, Sur C, Pettibone DJ, Conn PJ, Williams DL Jr (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64:731–740
Phillips T, Rees S, Augood S, Waldvogel H, Faull R, Svendsen C, Emson P (2000) Localization of metabotropic glutamate receptor type 2 in the human brain. Neuroscience 95:1139–1156
Pisani A, Calabresi P, Centonze D, Bernardi G (1997) Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br J Pharmacol 120:1007–1014
Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20
Schoepp DD, Conn PJ (2002) Metabotropic glutamate receptors. Pharmacol Biochem Behav 74:255–256
Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ (2003) LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6:189–197
Sladeczek F, Pin JP, Recasens M, Bockaert J, Weiss S (1985) Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317:717–719
Sugiyama H, Ito I, Hirono C (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325:531–533
Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503
Tamminga CA (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21–36
Vardi N, Duvoisin R, Wu G, Sterling P (2000) Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. J Comp Neurol 423:402–412
Weinberger D, Berman K, Zec R (1986) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence. Arch Gen Psychiatry 43:114–125
Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE (2001) Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825–844
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Moghaddam, B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology 174, 39–44 (2004). https://doi.org/10.1007/s00213-004-1792-z
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DOI: https://doi.org/10.1007/s00213-004-1792-z