Imaging glutamate in schizophrenia: Review of findings and implications for drug discovery

Molecular Psychiatry

Volumn 19, Issue 1, 2014, Pages 20-29

  Poels, E M P ^a   Kegeles, L S ^a   Kantrowitz, J T ^a   Slifstein, M ^a   Javitt, D C ^a   Lieberman, J A ^a   Abi Dargham, A ^a,b   Girgis, R R ^a  

^a NEW YORK STATE PSYCHIATRIC INSTITUTE   (United States)

^b New York State Psychiatric Institute ^*  (United States)

Author keywords

Glutamate; glutathione; magnetic resonance spectroscopy (MRS); NMDA; positron emission tomography (PET); schizophrenia

Indexed keywords

4 AMINOBUTYRIC ACID; DOPAMINE; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; GLUTAMIC ACID; GLUTAMINE; GLUTATHIONE; GLYCINE; KETAMINE; METABOTROPIC RECEPTOR 5; N METHYL DEXTRO ASPARTIC ACID RECEPTOR;

ANTERIOR CINGULATE; BASAL GANGLION; CEREBELLUM; DOPAMINE RELEASE; HIPPOCAMPUS; HUMAN; MEDIAL PREFRONTAL CORTEX; MEDIAL TEMPORAL LOBE; NONHUMAN; OCCIPITAL LOBE; PARIETAL LOBE; POSITRON EMISSION TOMOGRAPHY; PREFRONTAL CORTEX; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; REVIEW; SCHIZOPHRENIA; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; TEMPORAL LOBE; THALAMUS;

ANIMALS; DRUG DISCOVERY; GLUTAMIC ACID; HUMANS; NEUROIMAGING; SCHIZOPHRENIA;

EID: 84891155212     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/mp.2013.136     Document Type: Review

References (138)

1. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: an update and critical review of the pharmacology and clinical profiles of current and future therapeutic agents. Mol Psychiatry 2012; 17: 1206-1227.
2. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79-104.
3. Baker DA, Madayag A, Kristiansen LV, Meador-Woodruff JH, Haroutunian V, Raju I. Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacology 2008; 33: 1760-1772.
4. Kantrowitz JT, Javitt DC. N-methyl-d-Aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 2010; 83: 108-121.
5. Singh SP, Singh V. Meta-Analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011; 25: 859-868.
6. Pinard E, Alanine A, Alberati D, Bender M, Borroni E, Bourdeaux P et al. Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin- 2-yl)piperazin- 1-yl][5-methanesulfonyl-2-( (S)-2,2,2-trifluoro-1-methylethoxy) phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia. J Med Chem 2010; 53: 4603-4614.
7. Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med 2011; 3: 102mr102.
8. Luby ED, Gottlieb JS, Cohen BD, Rosenbaum G, Domino EF. Model psychoses and schizophrenia. Am J Psychiatry 1962; 119: 61-67.
9. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301-1308.
10. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214.
11. Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D et al. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 1999; 156: 1646-1649.
12. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 2001; 25: 455-467.
13. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D et al. Ketamineinduced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997; 17: 141-150.
14. Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987; 91: 415-433.
15. Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 1995; 346: 1130-1131.
16. McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [F-18]fluorodopa study. Arch Gen Psychiat 2004; 61: 134-142.
17. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F et al. Elevated Dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA 1994; 91: 11651-11654.
18. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235-9240.
19. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761-767.
20. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569-2574.
21. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104-8109.
22. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660-669.
23. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-1486.
24. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002; 22: 3708-3719.
25. Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban NB et al. Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112. J Psychopharmacol 2011; 26: 794-805.
26. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997; 385: 634-636.
27. Karlsson P, Farde L, Halldin C, Sedvall G. PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002; 159: 761-767.
28. Javitt DC, Hashim A, Sershen H. Modulation of striatal dopamine release by glycine transport inhibitors. Neuropsychopharmacology 2005; 30: 649-656.
29. Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 1998; 18: 18-25.
30. Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 1998; 29: 142-147.
31. Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 2000; 34: 35-43.
32. Aalto S, Hirvonen J, Kajander J, Scheinin H, Nagren K, Vilkman H et al. Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl) 2002; 164: 401-406.
33. Kegeles LS, Martinez D, Kochan LD, Hwang DR, Huang Y, Mawlawi O et al. NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse 2002; 43: 19-29.
34. Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H et al. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology 2005; 182: 375-383.
35. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 2000; 48: 627-640.
36. Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M et al. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 2005; 162: 2352-2359.
37. Miller DW, Abercrombie ED. Effects of MK-801 on spontaneous and amphetamine- stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats. Brain Res Bull 1996; 40: 57-62.
38. Galinska B, Szulc A, Tarasow E, Kubas B, Dzienis W, Czernikiewicz A et al. Duration of untreated psychosis and proton magnetic resonance spectroscopy (1H-MRS) findings in first-episode schizophrenia. Med Sci Monit 2009; 15: CR82-CR88.
39. Goto N, Yoshimura R, Kakeda S, Nishimura J, Moriya J, Hayashi K et al. Six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia. Neuropsychiatr Dis Treat 2012; 8: 119-122.
40. Ohrmann P, Kugel H, Bauer J, Siegmund A, Kolkebeck K, Suslow T et al. Learning potential on the WCST in schizophrenia is related to the neuronal integrity of the anterior cingulate cortex as measured by proton magnetic resonance spectroscopy. Schizophr Res 2008; 106: 156-163.
41. da Silva Alves F, Boot E, Schmitz N, Nederveen A, Vorstman J, Lavini C et al. Proton magnetic resonance spectroscopy in 22q11 deletion syndrome. PLoS One 2011; 6: e21685.
42. Szulc A, Galinska B, Tarasow E, Waszkiewicz N, Konarzewska B, Poplawska R et al. Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment. Pharmacopsychiatry 2011; 44: 148-157.
43. Rowland LM, Spieker EA, Francis A, Barker PB, Carpenter WT, Buchanan RW. White matter alterations in deficit schizophrenia. Neuropsychopharmacology 2009; 34: 1514-1522.
44. Block W, Bayer TA, Tepest R, Traber F, Rietschel M, Muller DJ et al. Decreased frontal lobe ratio of N-Acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study. Neurosci Lett 2000; 289: 147-151.
45. Seese RR, O'Neill J, Hudkins M, Siddarth P, Levitt J, Tseng B et al. Proton magnetic resonance spectroscopy and thought disorder in childhood schizophrenia. Schizophr Res 2011; 133: 82-90.
46. Yoo SY, Yeon S, Choi CH, Kang DH, Lee JM, Shin NY et al. Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus. Schizophr Res 2009; 111: 86-93.
47. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X et al. Elevated prefrontal cortex gamma-Aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012; 69: 449-459.
48. Olbrich HM, Valerius G, Rusch N, Buchert M, Thiel T, Hennig J et al. Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study. World J Biol Psychiatry 2008; 9: 59-63.
49. van Elst LT, Valerius G, Buchert M, Thiel T, Rusch N, Bubl E et al. Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biol Psychiatry 2005; 58: 724-730.
50. Rusch N, Tebartz van Elst L, Valerius G, Buchert M, Thiel T, Ebert D et al. Neurochemical and structural correlates of executive dysfunction in schizophrenia. Schizophr Res 2008; 99: 155-163.
51. Stanley JA, Williamson PC, Drost DJ, Rylett RJ, Carr TJ, Malla A et al. An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 1996; 22: 597-609.
52. Ohrmann P, Siegmund A, Suslow T, Spitzberg K, Kersting A, Arolt V et al. Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res 2005; 73: 153-157.
53. Ohrmann P, Siegmund A, Suslow T, Pedersen A, Spitzberg K, Kersting A et al. Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. J Psychiatr Res 2007; 41: 625-634.
54. Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J et al. Glutamate and glutamine measured with 4.0T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry 2002; 159: 1944-1946.
55. Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L et al. Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1997; 54: 959-965.
56. Theberge J, Williamson KE, Aoyama N, Drost DJ, Manchanda R, Malla AK et al. Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. Br J Psychiatry 2007; 191: 325-334.
57. Aoyama N, Theberge J, Drost DJ, Manchanda R, Northcott S, Neufeld RW et al. Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. Br J Psychiatry 2011; 198: 448-456.
58. Bustillo JR, Chen H, Gasparovic C, Mullins P, Caprihan A, Qualls C et al. Glutamate as a marker of cognitive function in schizophrenia: a proton spectroscopic imaging study at 4 Tesla. Biol Psychiatry 2011; 69: 19-27.
59. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM et al. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 2008; 64: 718-726.
60. Wood SJ, Yucel M, Wellard RM, Harrison BJ, Clarke K, Fornito A et al. Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: a proton magnetic resonance spectroscopy study at 3T. Schizophr Res 2007; 94: 328-331.
61. Kraguljac NV, Reid MA, White DM, den Hollander J, Lahti AC. Regional decoupling of N-Acetyl-Aspartate and glutamate in schizophrenia. Neuropsychopharmacology 2012; 37: 2635-2642.
62. Bustillo JR, Rowland LM, Mullins P, Jung R, Chen H, Qualls C et al. 1H-MRS at 4 tesla in minimally treated early schizophrenia. Mol Psychiatry 2010; 15: 629-636.
63. Reid MA, Stoeckel LE, White DM, Avsar KB, Bolding MS, Akella NS et al. Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia. Biol Psychiatry 2010; 68: 625-633.
64. Choe BY, Suh TS, Shinn KS, Lee CW, Lee C, Paik IH. Observation of metabolic changes in chronic schizophrenia after neuroleptic treatment by in vivo hydrogen magnetic resonance spectroscopy. Invest Radiol 1996; 31: 345-352.
65. Szulc A, Galinska B, Tarasow E, Dzienis W, Kubas B, Konarzewska B et al. The effect of risperidone on metabolite measures in the frontal lobe, temporal lobe, and thalamus in schizophrenic patients. A proton magnetic resonance spectroscopy (1H MRS). Pharmacopsychiatry 2005; 38: 214-219.
66. Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK et al. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 2012; 37: 2515-2521.
67. Thomas MA, Ke Y, Levitt J, Caplan R, Curran J, Asarnow R et al. Preliminary study of frontal lobe 1H MR spectroscopy in childhood-onset schizophrenia. J Magn Reson Imaging 1998; 8: 841-846.
68. Chang L, Friedman J, Ernst T, Zhong K, Tsopelas ND, Davis K. Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Biol Psychiatry 2007; 62: 1396-1404.
69. Ota M, Ishikawa M, Sato N, Hori H, Sasayama D, Hattori K et al. Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation. Acta Psychiatr Scand 2012; 126: 72-78.
70. Hutcheson NL, Reid MA, White DM, Kraguljac NV, Avsar KB, Bolding MS et al. Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging. Schizophr Res 2012; 140: 136-142.
71. Bartha R, al-Semaan YM, Williamson PC, Drost DJ, Malla AK, Carr TJ et al. A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients. Biol Psychiatry 1999; 45: 1403-1411.
72. Fusar-Poli P, Stone JM, Broome MR, Valli I, Mechelli A, McLean MA et al. Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. Arch Gen Psychiatry 2011; 68: 881-890.
73. Valli I, Stone J, Mechelli A, Bhattacharyya S, Raffin M, Allen P et al. Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis. Biol Psychiatry 2011; 69: 97-99.
74. Theberge J, Al-Semaan Y, Jensen JE, Williamson PC, Neufeld RW, Menon RS et al. Comparative study of proton and phosphorus magnetic resonance spectroscopy in schizophrenia at 4 Tesla. Psychiatry Res 2004; 132: 33-39.
75. Keshavan MS, Dick RM, Diwadkar VA, Montrose DM, Prasad KM, Stanley JA. Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: a (1)H spectroscopy study. Schizophr Res 2009; 115: 88-93.
76. Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ et al. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry 2009; 66: 533-539.
77. de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S, Mamo D, Ramirez- Bermudez J et al. Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with firstepisode psychosis. Neuropsychopharmacology 2011; 36: 1781-1791.
78. Tayoshi S, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J et al. Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS). Schizophr Res 2009; 108: 69-77.
79. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Stephano S, Favila R, Diaz- Galvis L et al. Glutamate in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episodepsychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 2013; 70: 1057-1066.
80. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Favila R, Stephano S, Graff- Guerrero A. Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study. Int J Neuropsychopharmacol 2013; 16: 471-475.
81. Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ et al. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine- induced psychopathology. Mol Psychiatry 2012; 17: 664-665.
82. Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 2005; 162: 394-396.
83. Taylor MJ, Tiangga ER, Mhuircheartaigh RN, Cowen PJ. Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: a proton magnetic resonance spectroscopy study. J Psychopharmacol 2012; 26: 733-737.
84. Bressan RA, Erlandsson K, Mulligan RS, Gunn RN, Cunningham VJ, Owens J et al. Evaluation of NMDA receptors in vivo in schizophrenic patients with [123I]CNS 1261 and SPET: preliminary findings. Ann NY Acad Sci 2003; 1003: 364-367.
85. Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ et al. Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-Aspartate receptors in vivo. Biol Psychiatry 2005; 58: 41-46.
86. Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 2006; 11: 118-119.
87. Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA et al. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study. Psychopharmacology 2008; 197: 401-408.
88. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533-1539.
89. Dean O, Giorlando F, Berk M. N-Acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36: 78-86.
90. Kohr G, Eckardt S, Luddens H, Monyer H, Seeburg PH. NMDA receptor channels: subunit-specific potentiation by reducing agents. Neuron 1994; 12: 1031-1040.
91. Atkuri KR, Mantovani JJ, Herzenberg LA. N-Acetylcysteine-A safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7: 355-359.
92. Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ. Nacetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry 2012; 71: 1006-1014.
93. Steullet P, Neijt HC, Cuenod M, Do KQ. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 2006; 137: 807-819.
94. Dean O, Bush AI, Berk M, Copolov DL, van den Buuse M. Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice. Behav Brain Res 2009; 198: 258-262.
95. Cruz-Aguado R, Almaguer-Melian W, Diaz CM, Lorigados L, Bergado J. Behavioral and biochemical effects of glutathione depletion in the rat brain. Brain Res Bull 2001; 55: 327-333.
96. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I et al. N-Acetyl cysteine as a glutathione precursor for schizophrenia-A double-blind, randomized, placebo- controlled trial. Biol Psychiatry 2008; 64: 361-368.
97. Wood SJ, Berger GE, Wellard RM, Proffitt TM, McConchie M, Berk M et al. Medial temporal lobe glutathione concentration in first episode psychosis: a 1H-MRS investigation. Neurobiol Dis 2009; 33: 354-357.
98. Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000; 12: 3721-3728.
99. Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E et al. Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS One 2008; 3: e1944.
100. Terpstra M, Vaughan TJ, Ugurbil K, Lim KO, Schulz SC, Gruetter R. Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia. MAGMA 2005; 18: 276-282.
101. Trabesinger AH, Boesiger P. Improved selectivity of double quantum coherence filtering for the detection of glutathione in the human brain in vivo. Magn Reson Med 2001; 45: 708-710.
102. Zhao T, Heberlein K, Jonas C, Jones DP, Hu X. New double quantum coherence filter for localized detection of glutathione in vivo. Magn Reson Med 2006; 55: 676-680.
103. Huang HL, Yeh CN, Chang KW, Chen JT, Lin KJ, Chiang LW et al. Synthesis and evaluation of [18F]Fluorobutyl ethacrynic amide: a potential PET tracer for studying glutathione transferase. Bioorg Med Chem Lett 2012; 22: 3998-4003.
104. Caglar M, Ciftci I, Hosal S, Kilinc K, Ercan MT. Detection of head and neck cancer with 99Tc(m) glutathione: a correlative study with tissue glutathione and glutathione S-transferase levels. Nucl Med Commun 2001; 22: 33-38.
105. Gunn RN, Murthy V, Catafau AM, Searle G, Bullich S, Slifstein M et al. Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1. Synapse 2011; 65: 1319-1332.
106. Bullich S, Slifstein M, Passchier J, Murthy NV, Kegeles LS, Kim JH et al. Biodistribution and radiation dosimetry of the glycine transporter-1 ligand 11C-GSK931145 determined from primate and human whole-body PET. Mol Imaging Biol 2011; 13: 776-784.
107. Wong DF, Ostrowitzki S, Zhou Y, Raymont V, Hofmann C, Borroni E et al. Characterization of [(11)C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans. Neuroimage 2011; 15: 282-290.
108. Martin-Facklam M, Pizzagalli F, Zhou Y, Ostrowitzki S, Raymont V, Brasic JR et al. Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers. Neuropsychopharmacology 2013; 38: 504-512.
109. Zheng M, Holden D, Hamill T, Lin S, Ropchan J, Najafzadeh S et al. Comparative study of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK6577 in baboons. J Nucl Med Meeting Abstracts 2013; 54: 414.
110. Hamill TG, Eng W, Jennings A, Lewis R, Thomas S, Wood S et al. The synthesis and preclinical evaluation in rhesus monkey of [(1)(8)F]MK-6577 and [(1)(1)C]CMPyPB glycine transporter 1 positron emission tomography radiotracers. Synapse 2011; 65: 261-270.
111. Chavez-Noriega LE, Schaffhauser H, Campbell UC. Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. Curr Drug Targets CNS Neurol Disord 2002; 1: 261-281.
112. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9: 984-997979.
113. Pisani A, Bernardi G, Bonsi P, Centonze D, Giacomini P, Calabresi P. Cell-type specificity of mGluR activation in striatal neuronal subtypes. Amino Acids 2000; 19: 119-129.
114. Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-Aspartate responses in medium spiny striatal neurons. Neuroscience 2001; 106: 579-587.
115. Krystal JH, Mathew SJ, D'Souza DC, Garakani A, Gunduz-Bruce H, Charney DS. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 2010; 24: 669-693.
116. Ehlers MD. Synapse structure: glutamate receptors connected by the shanks. Curr Biol 1999; 9: R848-R850.
117. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 1999; 23: 569-582.
118. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 1999; 23: 583-592.
119. Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G et al. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piper idin-1-yl}- methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther 2008; 327: 827-839.
120. Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS, McNaughton CH et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 2009; 57: 531-538.
121. Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 2009; 34: 2057-2071.
122. Koros E, Rosenbrock H, Birk G, Weiss C, Sams-Dodd F. The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 2007; 32: 562-576.
123. Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 1997; 17: 5196-5205.
124. Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 2003; 306: 116-123.
125. Brody SA, Conquet F, Geyer MA. Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology (Berl) 2004; 172: 187-195.
126. Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A. The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 2002; 43: 1199-1209.
127. Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S et al. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med 2006; 47: 698-705.
128. Delorenzo C, Kumar JS, Mann JJ, Parsey RV. In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [(11)C]ABP688. J Cereb Blood Flow Metab 2011; 31: 2169-2180.
129. Miyake N, Skinbjerg M, Easwaramoorthy B, Kumar D, Girgis RR, Xu X et al. Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-Acetylcysteine challenge. Biol Psychiatry 2011; 69: 822-824.
130. Elmenhorst D, Aliaga A, Bauer A, Rosa-Neto P. Test-retest stability of cerebral mGluR(5) quantification using [(1)(1)C]ABP688 and positron emission tomography in rats. Synapse 2012; 66: 552-560.
131. DeLorenzo C, Milak MS, Brennan KG, Kumar JS, Mann JJ, Parsey RV. In vivo positron emission tomography imaging with [(1)(1)C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. Eur J Nucl Med Mol Imaging 2011; 38: 1083-1094.
132. Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry 2012; 73: 161-168.
133. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. Am J Psychiatry 2011; 168: 727-734.
134. Sullivan JM, Lim K, Labaree D, Lin SF, McCarthy TJ, Seibyl JP et al. Kinetic analysis of the metabotropic glutamate subtype 5 tracer [(18)F]FPEB in bolus and bolusplus- constant-infusion studies in humans. J Cereb Blood Flow Metab 2013; 33: 532-541.
135. Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W et al. FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med 2013; 54: 388-396.
136. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D-2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157: 514-520.
137. Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects-A double-blind pet study of schizophrenic-patients. Biol Psychiatry 1993; 33: 227-235.
138. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31: 349-355.