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The Role of Glutamate in Anxiety and Related Disorders

Published online by Cambridge University Press:  07 November 2014

Bernadette M. Cortese  and
K. Luan Phan
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Abstract

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the γ-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.

Type
Review Articles
Information
CNS Spectrums , Volume 10 , Issue 10 , October 2005 , pp. 820 - 830
Copyright
Copyright © Cambridge University Press 2005

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References

REFERENCES

1.Greenberg, PE, Sisitsky, T, Kessler, RC, et al.The economic hurden of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60:427–435.CrossRefGoogle Scholar
2.Lepine, JP. The epidemiology of anxiety disorders: prevalence and societal costs. J Clin Psychiatry. 2002;63(suppl 14):4–8.Google ScholarPubMed
3.Marciniak, M, Lage, MJ, Landbloom, RP, Dunayevich, E, Bowman, L. Medical and productivity costs of anxiety disorders: case control study. Depress Anxiety. 2004;19;112–120.CrossRefGoogle ScholarPubMed
4.Liberzon, I, Phan, KL, Khan, S, Abelson, JL. Role of GABA-A receptors in anxiety: Evidence from animal models, clinical psychopharmacology, and neuroimaging studies. Current Neuropharmacology. 2003;1:267–283.CrossRefGoogle Scholar
5.Hamner, MB, Robert, S, Frueh, BC. Treatment-resistant posttraumatic stress disorder: strategies for intervention. CNS Spectr. 2004;9:740–752.Google Scholar
6.van Ameringen, M, Mancini, C, Pipe, B, Bennett, M. Optimizing treatment in social phobia: a review of treatment resistance. CNS Spectr. 2004;9:753–762.CrossRefGoogle ScholarPubMed
7.Keller, MB, Hirschfeld, RM, Demyttenaere, K, Baldwin, DS. Optimizing outcomes in depression: focus on antidepressant compliance. Int Clin Psychopharmacol. 2002;17:265–271.CrossRefGoogle ScholarPubMed
8.Gorman, JM. New molecular targets for antianxiety interventions. J Clin Psychiatry. 2003;64:28–35.Google ScholarPubMed
9.Lujan, R, Shigemoto, R, Lopez-Bendito, G. Glutamate and GABA receptor signalling in the developing brain. Neuroscience. 2005;130:567–580.CrossRefGoogle ScholarPubMed
10.Stanton, PK. LTD, LTP, and the sliding threshold for long-term synaptic plasticity. Hippocampus. 1996;6:35–42.Google Scholar
11.Swan, JH, Meldrum, BS. Protection by NMDA antagonists against selective cell loss following transient ischaemia. J Ccreb Blood Flow Metab. 1990;10:343–351.Google Scholar
12.Hynd, MR, Scott, HL, Dodd, PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem Int. 2004;45:583–595.CrossRefGoogle ScholarPubMed
13.Meldrum, BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S suppl):1007S–1015S.CrossRefGoogle ScholarPubMed
14.Kew, JN, Kemp, JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychnpharmacology (Bed). 2005;179:4–29.CrossRefGoogle ScholarPubMed
15.Krystal, JH, D'Souza, DC, Petrakis, IL, et al.NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv Rev Psychiatry. 1999;7:125–143.Google Scholar
16.Swanson, CJ, Bures, M, Johnson, MP, Linden, AM, Monn, JA, Schoepp, DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov. 2005;4:131–144.CrossRefGoogle ScholarPubMed
17.Conn, PJ, Pin, JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205–237.CrossRefGoogle ScholarPubMed
18.LeDoux, JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155–184.CrossRefGoogle ScholarPubMed
19.Davis, M. The role of the amygdala in fear-potentiated startle: implications for animal models of anxiety. Trends Pharmacol Sci. 1992;13:35–41.CrossRefGoogle ScholarPubMed
20.Adolphs, R. Neural systems for recognizing emotion. Curr Opin Neurobiol. 2002;12:169–177.Google Scholar
21.Cannistraro, PA, Rauch, SL. Neural circuitry of anxiety: evidence from structural and functional neuroimaging studies. Psychopharmacol Bull. 2003;37:8–25.Google Scholar
22.McDonald, AJ. Glutamate and aspartate immunoreactive neurons of the rat basolateral amygdala: colocalization of excitatory amino acids and projections to the limbic circuit. J Comp Neurol. 1996;365:367–379.3.0.CO;2-2>CrossRefGoogle Scholar
23.Mathew, SJ, Coplan, JD, Schoepp, DD, Smith, EL, Rosenblum, LA, Gorman, JM. Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders. CNS Spectr. 2001;6:555–564.Google Scholar
24.Jedema, HP, Moghddam, B. Characterization of excitatory amino acid modulation of dopa- mine release in the prefrontal cortex of conscious rats. J Neurochem. 1996;66:1448–1453.Google Scholar
25.Takahata, R, Moghaddam, B. Glutamatergic regulation of basal and stimulus-activated 54-dopamine release in the prefrontal cortex. J Neurochem. 1998;71:1443–1449.CrossRefGoogle ScholarPubMed
26.Becquet, D, Hery, M, Francois-Bellan, AM, et al.Glutamate, GABA, glycine and taurine modulate serotonin synthesis and release in rostral and caudal rhombencephalic raphe cells in primary cultures. Neurochem Int. 1993;23:269–283.CrossRefGoogle ScholarPubMed
27.Cheramy, A, Romo, R, Godeheu, G, Baruch, P, Glowinski, J. In vivo presynaptic control of dopamine release in the cat caudate nucleus–II. Facilttatory or inhibitory influence of 57. L-glutamate. Neuroscience. 1986;19:1081–1090.CrossRefGoogle ScholarPubMed
28.Okada, M, Yosbida, S, Zbu, G, Hirose, S, Kaneko, S. Biphasic actions of topiramate on monoamine exocytosis associated with both soluble N-ethylmaleimide-sensitive factor attachment protein receptors and Ca(2+)-induced Ca(2+)-releasing systems. Neuroscience. 2005;134:233–246.CrossRefGoogle ScholarPubMed
29.Ahmad, S, Fowler, LJ, Whitton, PS. Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids. Epilepsy Res. 2005;63:141–149.Google Scholar
30.Cunningham, MO, Jones, RS. The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology. 2000;39:2139–2146.Google Scholar
31.Sapolsky, RM. Stress and plasticity in the limbic system. Neurochem Res. 2003;28:1735–1742.Google Scholar
32.Fontella, FU, Vendite, DA, Tabajara, AS, et al.Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem Res. 2004;29:1703–1709.Google Scholar
33.Gilad, GM, Gilad, VH, Wyatt, RJ, Tizabi, Y. Region-selective stress-induced increase of glutamate uptake and release in rat forebrain. Brain Res. 1990;525:335–338.Google Scholar
34.Lowy, MT, Wittenberg, L, Yamamoto, BK. Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J Neurochem. 1995;65:268–274.CrossRefGoogle Scholar
35.Moghaddam, B. Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem. 1993;60:1650–1657.CrossRefGoogle ScholarPubMed
36.Schwendt, M, Jezova, D. Gene expression of two glutamate receptor subunits in response to repeated stress exposure in rat hippocampus. Cell Mol Neurobiol. 2000;20:319–329.Google Scholar
37.McEwen, BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–122.Google Scholar
38.Magarinos, AM, McEwen, BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience. 1995;69:89–98.CrossRefGoogle ScholarPubMed
39.Vyas, A, Mitra, R, Shankaranarayana Rao, BS, Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22:6810–6818.Google Scholar
40.Vyas, A, Bernal, S, Chattarji, S. Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res. 2003;965:290–294.Google Scholar
41.Herman, JP, Cullinan, WE. Neurocircuitry of stress: central control of the hypothalamopituitary-adrenocortical axis. Trends Neurosci. 1997;20:78–84.Google Scholar
42.Shors, Tj, Weiss, C, Thompson RE Stress-induced facilitation of classical conditioning. Science. 1992;257:537–539.CrossRefGoogle Scholar
43.Shors, TJ, Mathew, PR. NMDA receptor antagonism in the lateral/basolateral but not central nucleus of the amygdala prevents the induction of facilitated learning in response to stress. Learn Mem. 1998;5:220–230.Google Scholar
44.Luine, V, Villegas, M, Martinez, C, McEwen, BS. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 1994;639:167–170.CrossRefGoogle ScholarPubMed
45.Isgor, C, Kabbaj, M, Akil, H, Watson, SJ. Delayed effects of chronic variable stress during 74-peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus. 2004;14:636–648.Google Scholar
46.Conrad, CD, LeDoux, JE, Magarinos, AM, McEwen, BS. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci. 1999;113:902–913.CrossRefGoogle ScholarPubMed
47.Bast, T, Zhang, WN, Feldon, J. Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation. Hippocampus. 2003;13:657–675.Google Scholar
48.Maren, S, Aharonov, G, Stote, DL, Fanselow, MS. N-hyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. Behav Neurosci. 1996;110:1365–1374.Google Scholar
49.Walker, DL, Davis, M. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav. 2002;71:379–392.Google Scholar
50.Chambers, RA, Bremner, JD, Moghaddam, B, Soutbwick, SM, Charney, DS, Krystal, JH. Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation. Semin Clin Neuropsychiatry. 1999;4:274–281.Google Scholar
51.Krystal, JH, Karper, LP, Seibyl, JP, 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.Google Scholar
52.Shekhar, A, McCann, UD, Meaney, MJ, et al.Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology (Berl). 2001;157:327–339.Google Scholar
53.Pellow, S, File, SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav. 1986;24:525–529.CrossRefGoogle Scholar
55.Geller, I. Effect of punishment on lever pressing maintained by food reward or brain stimulation. Physiol Behav. 1970;5:203–206.Google Scholar
55.Davis, M, Astrachan, DI. Conditioned fear and startle magnitude: effects of different footshock or backshock intensities used in training. J Exp Psychol Anim Behav Process. 1978;4:95–103.Google Scholar
56.Uhde, T, Galloway, M, Fang, J, et al.Sleep deprivation and excitatory amino acids. Neuropsychopharmacology. 2004;29:S213.Google Scholar
57.Mathew, SJ, Shungu, DC, Mao, X, et al.A magnetic resonance spectroscopic imaging study of adult nonhuman primates exposed to early-life stressors. Biol Psychiatry. 2003;54:727–735.CrossRefGoogle ScholarPubMed
58.Bartha, R, Drost, DJ, Menon, RS, Williamson, PC. Comparison of the quantification precision of human short echo time (1)H spectroscopy at 1.5 and 4.0 Tesla. Magn Reson Med. 2000;44:185–192.Google Scholar
59.Ke, Y, Cohen, BM, Bang, JY, Yang, M, Renshaw, PF. Assessment of GABA concentration in human brain using two-dimensional proton magnetic resonance spectroscopy. Psychiatry Res. 2000;100:169–178.Google Scholar
60.Kaiser, LG, Schuff, N, Cashdollar, N, Weiner, MW. Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging. 2005;26:665–672.Google Scholar
61.Stanley, JA, Drost, DJ, Williamson, PC, Thompson, RT. The use of a priori knowledge to quantify short echo in vivo 1H MR spectra. Magn Reson Med. 1995;34:17–24Google Scholar
62.Munro, LJ, Kokkinidis, L. Infusion of quinpirole and muscimol into the ventral tegmental area inhibits fear-potentiated startle: implications for the role of dopamine in fear expression. Brain Res. 1997;746:231–238.Google Scholar
63.Fendt, M, Koch, M, Schnitzler, HU. NMDA receptors in the pontine brainstem are necessary for fear potentiation of the startle response. Eur J Pharmacol. 1996;318:l–6.CrossRefGoogle ScholarPubMed
64.Campeau, S, Miserendino, MJ, Davis, M. Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus. Behav Neurosci. 1992;106:569–574.Google Scholar
65.Anthony, EW, Nevins, ME. Anxiolytic-like effects of N-methyl-D-aspartate-associated glycine receptor ligands in the rat potentiated startle test. Eur J Pharmacol. 1993;250:317–324.Google Scholar
66.Walker, DL, Ressler, KJ, Lu, KT, Davis, M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:2343–2351.Google Scholar
67.Parnas, AS, Weber, M, Richardson, R. Effects of multiple exposures to d-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem. 2005;83:224–231.Google Scholar
68.Ledgerwood, L, Richardson, R, Cranney, J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci. 2003;117:341–349.Google Scholar
69.Ledgerwood, L, Richardson, R, Cranney, J. D-cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement. Behav Neurosci. 2004;118:505–513.CrossRefGoogle ScholarPubMed
70.Fendt, M. Expression and conditioned inhibition of fear-potentiated startle after stimulation and blockade of AMPA/Kainate and GABA(A) receptors in the dorsal periaqueductal gray. Brain Res. 2000;880:1–10.Google Scholar
71.Rosenfeld, WE. Topiramate: a review of preclinical, pharmacokinetic, and clinical data. Clin Ther. 1997;19:1294–1308.Google Scholar
72.Khan, S, Liberzon, I. Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology (Berl). 2004;172:225–229.CrossRefGoogle Scholar
73.Czuczwar, SJ, Patsalos, PN. The new generation of GABA enhancers. Potential in the treatment of epilepsy. CNS Drugs. 2001;15:339–350.CrossRefGoogle ScholarPubMed
74.Walker, DL, Rattiner, LM, Davis, M. Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats. Behav Neurosci. 2002;116:1075–1083.Google Scholar
75.Ho, YJ, Hsu, LS, Wang CF, Hsuet al.Behavioral effects of d-cycloserine in rats: The role of anxiety level. Brain Res. 2005;1043:179–185.Google Scholar
76.Karcz-Kubicha, M, Jessa, M, Nazar, M, et al.Anxiolytic activity of glycine-B antagonists and partial agonists-no relation to intrinsic activity in the patch clamp. Neuropharmacology. 1997;36:1355–1367.Google Scholar
77.Klodzinska, A, Chojnacka-Wojcik, E. Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis. Psychopharmacology (Berl). 2000;152:224–228.Google Scholar
78.Xie, ZC, Buckner, E, Commissaris, RL. Anticonflict effect of MK-801 in rats: time course and chronic treatment studies. Pharmacol Biochem Behav. 1995;51:635–640.Google Scholar
79.Kotlinska, J, Liljequist, S. The putative AMPA receptor antagonist, LY326325, produces anxiolytic-like effects without altering locomotor activity in rats. Pharmacol Biochem Behav. 1998;60:119–124.Google Scholar
80.Schulz, B, Fendt, M, Gasparini, F, Lingenhohl, K, Kuhn, R, Koch, M. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology. 2001;41:1–7.Google Scholar
81.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.Google Scholar
82.Linden, AM, Greene, SJ, Bergeron, M, Schoepp, DD. Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions. Neuropsychopharmacology. 2004;29:502–513.Google Scholar
83.Shekhar, A, Keim, SR. LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology. 2000;39: 1139–1146.CrossRefGoogle ScholarPubMed
84.Helton, DR, Tizzano, JP, Monn, JA, Schoepp, DD, Kallman, MJ. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. Pharmacol Exp Ther. 1998;284:651–660.Google ScholarPubMed
85.Johnson, MP, Barda, D, Britton, TC, et al.Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in pre-clinical anxiety and psychosis model(s). Psychopharmacology (Berl). 2005;179:271–283.Google Scholar
86.Steckler, T, Lavreysen, H, Oliveira, AM, et al.Effects of mGlul receptor blockade on anxiety-related behaviour in the rat lick suppression test. Psychopharmacology (Berl). 2005;179:198–206.CrossRefGoogle Scholar
87.Mirza, NR, Bright, JL, Stanhope, KJ, Wyatt, A, Harrington, NR. Lamotrigine has an atnxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels? Psychopharmacology (Berl). 2005;180:159–168.Google Scholar
88.Tizzano, JP, Griffey, KI, Schoepp, DD. The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam. Pharmacol Biochem Behav. 2002;73:367–374.Google Scholar
89.Grillon, C, Cordova, J, Levine, LR, Morgan, CA 3rd. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology (Berl). 2003;168:446–454.Google Scholar
90.Levine, LR, Gaydos, B, Sheehan, D, Goddard, A, Feighner, J, Potter, W, Schoepp, D. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Neuropharmacology. 2001;43:294–295.Google Scholar
91.Kellner, M, Muhtz, C, Stark, K, Yassouridis, A, Ark, J, Wiedemann, K. Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Psychopharmacology (Berl). 2005;179:310–315.CrossRefGoogle Scholar
92.Bremner, JD, Mletzko, T, Welter, S, et al.Treatment of post-traumatic stress disorder with phenytoin: An open label pilot study. Neuropsychopharmacology. 2004;29:S91.Google Scholar
93.Heresco-Levy, U, Kremer, I, Javitt, DC, et al.Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2002;5:301–307.Google Scholar
94.Ressler, KJ, Rothbaum, BO, Tannenbaum, L, et al.Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:1136–1144.Google Scholar
95.Berlant, J, van Kammen, DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002;63:15–20.Google Scholar
96.Berlant, JL. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry. 2004;4:24.Google Scholar
97.van Ameringen, M, Mancini, C, Pipe, B, Oakman, J, Bennett, M. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry. 2004;65:1674–1678.Google Scholar
98.Coric, V, Taskiran, S, Pittenger, C, et al.Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58:424–428.Google Scholar
99.Mathew, SJ, Amiel, JM, Coplan, JD, Fitterling, HA, Sackeim, HA, Gorman, JM. Riluzole in generalized anxiety disorder: an open-label trial. Am J Psychiatry. In press.Google Scholar
100.Linden, AM, Shannon, H, Baez, M, Yu, JL, Koester, A, Schoepp, DD. Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice. Psychopharmacology (Berl). 2005;179:284–291.Google Scholar
101.Arnold, PD, Rosenberg, DR, Mundo, E, Tharmalingam, S, Kennedy, JL, Richter, MA. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology (Berl). 2004;174:530–538.Google Scholar
102.Chakrabarty, K, Bhattacharyya, S, Christopher, R, Khanna, S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005;30:1735–1740.Google Scholar
103.Cunningham, MO, Dhillon, A, Wood, SJ, Jones, RS. Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin. Neuroscience. 2000;95:343–351.Google Scholar
104.Richardson, R, Ledgerwood, L, Cranney, J. Facilitation of fear extinction by D-cycloserine: theotetical and clinical implications. Learn Mem. 2004;11:510–516.Google Scholar
105.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.Google Scholar
106.Yamasue, H, Kasai, K, Iwanami, A, et al.Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc Natl Acad Sci U S A. 2003;100:9039–9043.CrossRefGoogle ScholarPubMed
107.Rauch, SL, Shin, LM, Segal, E, et al.Selectively reduced regional cortical volumes in post-traumatic stress disorder. Neuroreport. 2003;14:913–916.Google ScholarPubMed
108.Bremner, JD, Randall, P, Scott, TM, et al.MRI-based measurement of hippocampat volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:973–981.Google Scholar
109.Bremner, JD, Vythilingam, M, Vermetten, E, et, al, MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and post-traumatic stress disorder. Am J Psychiatry. 2003;160:924–932.CrossRefGoogle Scholar
110.Fennema-Notestine, C, Stein, MB, Kennedy, CM, Archibald, SL, Jernigan, TL. Brain morphometry in female victims of intimate partner violence with and without posttramatic stress disorder. Biol Psychiatry. 2002;52:1089–1101.Google Scholar
111.Stein, MB, Koverola, C, Hanna, C, Torchia, MG, McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27:951–959.Google Scholar
112.Kitayama, N, Vaccarino, V, Kutner, M, Weiss, P, Bremner, JD. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord. 2005;88:79–86.Google Scholar
113.MacMillan, S, Szeszko, PR, Moore, GJ, et al.Increased amygdala: hippocampal volume ratios associated with severity of anxiety in pediatric major depression. J Child Adolesc Psychopharmacol. 2003;13:65–73.Google Scholar
114.De Bellis, MD, Casey, BJ, Dahl, RE, et al.A pilot study of amygdala volumes in pediatric generalized anxiety disorder. Biol Psychiatry. 2000;48:51–57.Google Scholar
115.Szeszko, PR, MacMillan, S, McMeniman, M, et al.Amygdala volume reductions in pediatric patients with obsessive-compulsive disorder treated with paroxetine: preliminary findings. Neuropsychopharmacology. 2004;29:826–832.Google Scholar
116.Nordahl, TE, Semple, WE, Gross, M, et al.Cerebral glucose merabolic differences in patients with panic disorder. Neuropsychopharmacology. 1990;3:261–272.Google Scholar
117.Britton, JC, Phan, KL, Taylor, SF, Fig, LM, Liberzon, I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry. 2005;57:832–840.Google Scholar
118.Stein, MB, Goldin, PR, Sareen, J, Zorritla, LT, Brown, GG. Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry. 2002;59:1027–1034.Google Scholar
119.Birbaumer, N, Grodd, W, Diedrich, O, et al.fMRI reveals amygdala activation to human faces in social phobics. Neuroreport. 1998;9:1223–1226.Google Scholar
120.Freeman, TW, Cardwell, D, Karson, CN, Komoroski, RA. In vivo proton magnetic resonance spectroscopy of the medial temporal lobes of subjects with combat-related posttraumatic stress disorder. Magn Reson Med. 1998;40:66–71.Google Scholar
121.DeBellis, MD, Keshavan, MS, Spencer, S, Hall, J. N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am J Psychiatry. 2000;157:1175–1177.Google Scholar
122.Brown, S, Freeman, T, Kimbrell, T, Cardwell, D, Komoroski, R. In vivo proton magnetic resonance spectroscopy of the medial temporal lobes of former prisoners of war with and without posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci. 2003;15:367–370.Google Scholar
123.Davidson, JR, Krishnan, KR, Charles, HC, et al.Magnetic resonance spectroscopy in social phobia: preliminary findings, J Clin Psychiatry. 1993;54:19–25.Google Scholar
124.Tupler, LA, Davidson, JR, Smith, RD, Lazeyras, F, Charles, HC, Krishnan, KR. A repeat proton magnetic resonance spectroscopy study in social phobia. Biol Psychiatry. 1997;42:419–424.Google Scholar
125.Mathew, SJ, Mao, X, Coplan, JD, et al.Dorsolateral prefronral cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. Am J Psychiatry. 2004;161:1119–1121.CrossRefGoogle ScholarPubMed
126.Grachev, ID, Apkarian, AV. Chemical mapping of anxiety in the brain of healthy humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region. Hum Brain Mapp. 2000;11:261–272.Google Scholar
127.Phan, KL, Fitzgerald, DA, Cortese, BM, Seraji-Bozorgzad, N, Tancer, ME, Moore, GJ. Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. Neuroreport. 2005;16:183–186.Google Scholar
128.Rosenberg, DR, MacMaster, FP, Keshavan, MS, Fitzgerald, KD, Stewart, CM, Moore, GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry. 2000;39:1096–1103.Google Scholar
129.Phan, KL, Fitzgerald, DA, Cortese, BM, et al.Response to emotionally salient faces and glutamate concentrations in the rostral anterior cingulate cortex in social phobia: preliminary combined spectroscopic and functional magnetic resonance imaging studies at 4 Telsa. Neuropsychopharmacology. 2004;29:S193.Google Scholar
130.Rosenberg, DR, Mirza, Y, Russell, A, et al.Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolesc Psychiatry. 2004;43:1146–1153.Google Scholar
131.Keshavan, MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res. 1999;33:513–521.Google Scholar
132.Rosenberg, DR, Keshavan, MS. A.E. Bennett Research Award. Toward a neurodevelopmental model of of obsessive-compulsive disorder. Biol Psychiatry. 1998;43:623–640.Google Scholar
133.Szeszko, PR, MacMillan, S, McMeniman, M, et al.Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. Am J Psychiatry. 2004;161:1049–1056.Google Scholar