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Emotional Learning and Glutamate: Translational Perspectives

Published online by Cambridge University Press:  07 November 2014

Abstract

Anxiety disorders are a common focus of clinical concern and certain forms of anxiety may be conceptualized as disorders of emotional learning. Behavior therapies effective in the treatment of anxiety are modeled on extinction training as a means of reducing pathological anxiety. The present understanding of human anxiety has been informed by preclinical research using rodent models to study the acquisition and extinction of fear. Glutamate appears to have a central role in both of these processes. The authors review this literature and discuss novel applications of D-cycloserine, a partial N-methyl-D-aspartate agonist, for the treatment of anxiety.

Type
Review Articles
Copyright
Copyright © Cambridge University Press 2005

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References

REFERENCES

1.Izard, CE. Basic emotions, relations among emotions, and emotion-cognition relations. Psychol Rev. 1992;99:561565.Google Scholar
2.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994Google Scholar
3.Greenberg, PE, Sisitsky, T, Kessler, RC, et al.The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60:427455.CrossRefGoogle ScholarPubMed
4.McEwen, BS, Wingfield, JC. The concept of allostasis in biology and biomediane. Horm Behav. 2003;43:215.Google Scholar
5.Davis, M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353375.CrossRefGoogle ScholarPubMed
6.Davis, M. The role of the amygdala in conditioned and unconditioned fear and anxiety. In: Aggleton, JP, ed. The Amygdala. Oxford, England: Oxford University Press. 2000;215287.Google Scholar
7.LeDoux, JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155184.Google Scholar
8.Fanselow, MS, LeDoux, JE. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron. 1999;23:229232.Google Scholar
9.McGaugh, JL, Cahill, L, Roozendaal, B. Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci U S A. 1996;93:1350813514.Google Scholar
10.LaBar, KS, Gatenby, JC, Gore, JC, LeDoux, JE, Phelps, EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron. 1998;20:937945.Google Scholar
11.Phelps, EA, O'Connor, KJ, Gatenby, JC, Gore, JC, Grillon, C, Davis, M. Activation of the left amygdala to a cognitive representation of fear. Nat Neurosci. 2001;4:437441.CrossRefGoogle ScholarPubMed
12.Whalen, PJ, Shin, LM, Mclnerney, SC, Fischer, H, Wright, CI, Rauch, SL. A functional MRI study of human amygdala responses to facial expressions of fear versus anger. Emotion. 2001;1:7083.Google Scholar
13.Rauch, SL, Whalen, PJ, Shin, LM, et al.Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000;47:769776.Google Scholar
14.Pitkanen, A. Connectivity of the rat amygdaloid complex. In: Aggleton, JP, ed. The Amygdala. Second Edition: A Functional Analysis. New York, NY: Oxford University Press; 2000:31116.Google Scholar
15.Bading, H, Segal, MM, Sucher, NJ, Dudek, H, Lipton, SA, Greenberg, ME. N-methyl-D-aspartate receptors are critical for mediating the effects of glutamate on intracellular calcium concentration and immediate early gene expression in cultured hippocampal neurons. Neuroscience. 1995;64:653664.Google Scholar
16.Mahanty, NK, Sah, P. Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala. Nature. 1998;394:683687.Google Scholar
17.Bauer, EP, Schafe, GE, LeDoux, JE. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci. 2002;22:52395249.Google Scholar
18.Ressler, KJ, Paschall, G, Zhou, XL, Davis, M. Regulation of synaptic plasticity genes during consolidation of fear conditioning. J Neurosci. 2002;22:78927902.Google Scholar
19.Schafe, GE, LeDoux, JE. Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci. 2000;20:RC96.Google Scholar
20.Schafe, GE, Nader, K, Blair, HT, LeDoux, JE. Memory coasolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 2001;24:540546.Google Scholar
21.Walker, DL, Davis, M. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav. 2002;71:379392.Google Scholar
22.Miserendino, MJ, Sananes, CB, Melia, KR, Davis, M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature. 1990;345:716718.Google Scholar
23.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;106:569574.Google Scholar
24.Walker, DL, Paschall, GY, Davis, M. Glutamate receptor antagonist infusions into the basolateral and medial amygdala reveal differential contributions to olfactory vs. context fear conditioning and expression. Learn Mem. 2005;12:120129.Google Scholar
25.Lee, H, Kim, JJ. Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats. J Neurosci. 1998;18:84448454.Google Scholar
26.Rodrigues, SM, Schafe, GE, LeDoux, JE. Intra-amygdala blockade of the nr2b sub-unit of the nmda receptor disrupts the acquisition but not the expression of fear conditioning. J Neurosci. 2001;21:68896896.Google Scholar
27.Fanselow, MS, Kim, JJ. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D, L-2-amino-5-phospho-novaleric acid to the hasolateral amygdala. Behav Neurosci. 1994;108:210212.Google Scholar
28.Maren, S, Fanselow, MS. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci. 1995;15:75487564.Google Scholar
29.Chenard, BL, Menniti, FS. Antagonists selective for NMDA receptors containing the NR2B subunit. Curr Pharm Des. 1999;5:381404.Google Scholar
30.Tang, YP, Shimizu, E, Duhe, GR, et al.Genetic enhancement of learning and memory in mice. Nature. 1999;401:6369.Google Scholar
31.Goosens, KA, Maren, S. NMDA receptors are essential for the acquisition, but not expression, of conditional fear and associative spike firing in the lateral amygdala. Eur J Neurosci. 2004;20:537548.Google Scholar
32.Isaac, JT, Crair, MC, Nicoll, RA, Malenka, RC. Silent synapses during development of thalamocortical inputs. Neuron. 1997;18:269280.Google Scholar
33.Poncer, JC, Estehan, JA, Malinow, R. Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II. J Neurosci. 2002;22:44064411.Google Scholar
34.Rumpel, S, LeDoux, J, Zador, A, Malinow, R. Postsynaptic receptor traffickingunderlying a form of associative learning. Science. 2005;308:8388.Google Scholar
35.McKernan, MG, Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature. 1997;390:607611.Google Scholar
36.Li, H, Rogawski, MA. GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro. Neuropharmacology. 1998;37:12791286.Google Scholar
37.Li, H, Chen, A, Xing, G, Wei, ML, Rogawski, MA. Kainate receptor-mediated het-erosynaptic facilitation in the amygdala. Nat Neurosci. 2001;4:612620.Google Scholar
38.Braga, MF, Amniadou-Anderjaska, V, Xie, J, Li, H. Bidirectional modulation of GABA release by presynaptic glutamate receptor 5 kainate receptors in the basolateral amygdala. J Neurosci. 2003;23:442452.Google Scholar
39.Ko, S, Zhao, MG, Toyoda, H, Qiu, CS, Zhuo, M. Altered behavioral responses to noxious stimuli and fear in glutamate receptor 5 (GluR5)- or GluR6-deficient mice. J Neurosci. 2005;25:977984.Google Scholar
40.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;116:10751083.Google Scholar
41.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. Psychopharmocology (Berl). 2003;168:446454.CrossRefGoogle ScholarPubMed
42.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;179:284291.Google Scholar
43.Lin, CH, Lee, CC, Huang, YC, Wang, SJ, Gean, PW. Activation of group II metabotropic glutamate receptors induces depotentiation in amygdala slices and reduces fear-potentiated startle in rats. Learn Mem. 2005;12:130137.Google Scholar
44.Rodrigues, SM, Bauer, EP, Farb, CR, Schafe, GE, LeDoux, JE. The group I metabotropic glutamate receptor mGluR5 is required for fear memory formation and long-term potentiation in the lateral amygdala. J Neurosci. 2002;22:52195229.Google Scholar
45.Fendt, M, Schmid, S. Metabotropic glutamate receptors are involved in amygdaloid plasticity. Eur J Neurosci. 2002;15:15351541.Google Scholar
46.Busse, CS, Brodkin, J, Tattersall, D, et al.The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology. 2004;29:19711979.Google Scholar
47.Pavlov, I. Conditioned Reflexes. Oxford, England: Oxford University Press; 1927.Google Scholar
48.Rothbaum, BO, Davis, M. Applying learning principles to the treatment of post-trauma reactions. Ann N Y Acad Sci. 2003;1008:112121.Google Scholar
49.Bouton, ME. Context and behavioral processes in extinction. Learn Mem. 2004;11:485494.Google Scholar
50.Myers, KM, Davis, M. Behavioral and neural analysis of extinction. Neuron. 2002;36:567584.Google Scholar
51.Quirk, GJ, Russo, GK, Barron, JL, Lebron, K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci. 2000;20:62256231.Google Scholar
52.Milad, MR, Quirk, GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;420:7074.Google Scholar
53.Phelps, EA, Delgado, MR, Nearing, KI, LeDoux, JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004;43:897905.Google Scholar
54.Baker, JD, Azorlosa, JL. The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning. Behav Neurosci. 1996;110:618620.Google Scholar
55.Cox, J, Westbrook, REThe NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesia responses in the rat. Q J Exp Psychol B. 1994;47:187210.Google Scholar
56.Falls, WA, Miserendino, MJ, Davis, M. Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci. 1992;12:854863.Google Scholar
57.Santini, E, Muller, RU, Quirk, GJ. Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory. J Neurosci. 2001;21:90099017.Google Scholar
58.Lu, KT, Walker, DL, Davis, M. Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J Neurosci. 2001;21:RC162.Google Scholar
59.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;22:23432351.Google Scholar
60.Olney, J, New mechanisms of excitatory transmitter neurotoxicity. J Neural Transm Suppl. 1994;43:4751.Google Scholar
61.Ledgerwood, L, Richardson, R, Cranney, J. D-cycloserine facilitates extinction of learned fear: effects on reacquisition and genetalized extinction. Biol Psychiatry. 2005;57:841847.Google Scholar
62.Ledgerwood, L, Richardson, R, Cranney, J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci. 2003;117:341349.Google Scholar
63.Ledgerwood, L, Richardson, R, Cranney, J. D-cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement. Behav Neurosci 2004;118:505513.Google Scholar
64.Otto, M. Learning and “unlearning” fears: preparedness, neural pathways, and patients. Biol Psychiatry. 2002;52:917920.Google Scholar
65.Foa, EB, Franklin, ME, Moser, J. Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination? Biol Psychiatry. 2002;52:987997.Google Scholar
66.Barlow, DH, Gorman, JM, Shear, MK, Woods, SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial. JAMA. 2000;283:25292536.Google Scholar
67.Marks, IM, Swinson, RP, Basoglu, M, et al.Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Br J Psychiatry. 1993;162:776787.Google Scholar
68.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;61:136144.Google Scholar
69.Rothbaum, BO, Hodges, LF, Kooper, R, Opdyke, D, Williford, JS, North, M. Effectiveness of computer-generated (virtual reality) graded exposure in the treatment of acrophobia. Am J Psychiatry. 1995;152:626628.Google Scholar
70.Rothbaum, BO, Hodges, L, Smith, S, Lee, JH, Price, L. A controlled study of virtual reality exposure therapy for the fear of flying. J Consult Clin Psychol. 2000;68:10201026.Google Scholar
71.Rothbaum, BO, Hodges, LF, Ready, D, Graap, K, Alarcon, RD. Virtual reality exposure therapy for Vietnam veterans with posttraumatic stress disorder. J Clin Psychiatry. 2001;62:617622.Google Scholar
72.McGaugh, JL. Memory—a century of consolidation. Science. 200;287:248251.Google Scholar
73.Wilensky, AE, Schafe, GE, LeDoux, JE. The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. J Neurosci. 2000;20:70597066.Google Scholar