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D-cycloserine Inhibits Amygdala Responses During Repeated Presentations of Faces

  • Jennifer C. Britton, Andrea L. Gold, Eric J. Feczko, Scott L. Rauch, Danielle Williams and Christopher I. Wright...


Introduction: Recently, human studies using exposure therapy to treat anxiety have demonstrated that pretreatment with D-cycloserine (DCS) enhances fear reduction in anxiety disorders. However, the underlying brain mechanisms mediating this fear reduction have yet to be determined.

Methods: The effects of orally administered DCS on amygdala activity during the processing of repeated facial expressions were examined in this double-blind study. Fourteen healthy males (30.0±8.7 years of age) randomly received DCS 500 mg or placebo prior to 3.0 Tesla functional magnetic resonance imaging acquisition. All participants viewed four separate runs, consisting of a single block of a repeated facial expression (happy or fearful) bracketed by fixation blocks.

Results: Anatomic region-of-interest analyses showed that the placebo group exhibited amygdala activation and response habituation, while the DCS group displayed blunted amygdala responses to emotional faces across the experiment, whereby habituation was not detected.

Conclusion: This finding may have relevance for testing treatments of anxiety and depression.


Corresponding author

Please direct all correspondence to: Christopher I. Wright, MD, PhD, Laboratory of Aging and Emotion, Psychiatric Neuroimaging Research Program, Massachusetts General Hospital, Thirteenth Street, Building 149, CNY-2628, Charlestown, MA 02129; Tel: 617-724-2324, Fax: 617-726-4078; E-mail:


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1.Wright, Cl, Fischer, H, Whalen, PJ, McInerney, SC, Shin, LM, Rauch, SL. Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli. Neuroreport. 2001;12:379383.
2.Falls, WA, Miserendino, MJ, Davis, M, et al.Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci. 1992;12:854863.
3.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.
4.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.
5.Myers, KM, Davis, M. Behavioral and neural analysis of extinction. Neuron. 2002;36:567584.
6.Ledgerwood, L, Richardson, R, Cranney, J. Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci. 2003;117:341349.
7.Richardson, R, Ledgerwood, L, Cranney, J. Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications. Learn Mem. 2004;11:510516.
8.Hofmann, SG, Meuret, AE, Smits, JA, et al.Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry. 2006;63:298304.
9.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;61:11361144.
10.First, MB, Spitzer, RL, Gibbon, M, Williams, JB. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). New York, NY: Psychiatric Institute, Biometrics Research; 1995.
11.Beck, AT, Epstein, N, Brown, G, Steer, RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893897.
12.Beck, AT, Steer, RA. Beck Anxiety Inventory Manual. San Antonio, Tex: The Psychological Corporation, Harcourt Brace and Company; 1990.
13.Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J. An inventory for measuring depression. Arch Gen Psychiatry. 196;4:561571.
14.Spielberger, CD, Gorsuch, RL, Lushene, RD. STAI: Manual for the State-Trait Anxiety Inventory. Palo Alto, Calif: Consulting Psychologists Press; 1970.
15.Ekman, P, Friesen, WV. Pictures of Facial Affect. Palo Alto, Calif: Consulting Psychologists Press; 1976.
16.Crane, GE. Cyloserine as an antidepressant agent. Am J Psychiatry. 1959;115:10251026.
17.van Berckel, BN, Lipsch, C, Timp, S, et al.Behavioral and neuroendocrine effects of the partial NMDA agonist D-cycloserine in healthy subjects. Neuropsychopharmacology. 1997;16:317324.
18.Wedig, MM, Rauch, SL, Albert, MS, Wright, CI. Differential amygdala habituation to neutral faces in young and elderly adults. Neurosci Lett. 2005;385:114119.
19.Fischer, H, Wright, Cl, Whalen, PJ, McInerney, SC, Shin, LM, Rauch, SL. Brain habituation during repeated exposure to fearful and neutral faces: a functional MRI study. Brain Res Bull. 2003;59:387392.
20.Holt, DJ, Weiss, AP, Rauch, SL, et al.Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry. 2005;57:10111019.
21.Wright, Cl, Martis, B, Schwartz, CE. Novelty responses and differential effects of order in the amygdala, substantia innominata, and inferior temporal cortex. Neuroimage. 2003;18:660669.
22.Cox, RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162173.
23.Wright, CI, Williams, D, Feczko, E, et al.Neuroanatomical correlates of extraversion and neuroticism. Cereb Cortex. 2006;16:18091819.
24.Fischl, B, van der Kouwe, A, Destrieux, C, et al.Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004;14:1122.
25.Rauch, SL, Shin, LM, Wright, CI, et al.Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci. 2003;985:389410.
26.Shin, LM, Wright, Cl, Cannistraro, PA. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005;62:273281.
27.Birbaumer, N, Grodd, W, Diedrich, O. fMRI reveals amygdala activation to human faces in social phobics. Neuroreport. 1998;9:12231226.
28.Furmark, T, Tillfors, M, Marteinsdottir, I, et al.Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch Gen Psychiatry. 2002;59:425433.
29.Regier, DA, Boyd, JH, Burke, JD, et al.One-month prevalence of mental disorders in the United States. Based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry. 1988;45:977986.
30.Drevets, WC, Videen, TO, Price, JL, et al.A functional anatomical study of unipolar depression. J Neurosci. 1992;12:36283641.
31.Drevets, WC, Price, JL, Bardgett, ME, Reich, T, Todd, RD, Raichle, ME. Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels. Pharmacol Biochem Behav. 2002;71:431447.
32.Yurgelun-Todd, DA, Gruber, SA, Kanayama, G. fMRI during affect discrimination in bipolar affective disorder. Bipolar Disord. 2000;2:237248.
33.Drevets, WC, Bogers, W, Raichle, ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527544.
34.Sheline, YI, Barch, DM, Donnelly, JM, Ollinger, JM, Snyder, AZ, Mintun, MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50:651658.
35.Abel, KM, Allin, MP, Kucharska-Pietura, K. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport. 2003;14:387391.
36.Millan, MJ. N-methyl-D-aspartate receptor-coupled glycineB receptors in the pathogenesis and treatment of schizophrenia: a critical review. Curr Drug Targets CNS Neurol Disord. 2002;1:191213.
37.Zarate, CA, Singh, JB, Carlson, PJ, et al.A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856864.
38.Parnas, AS, Weber, M, Richardson, R, et al.Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem. 2005;83:224231.
39.Quartermain, D, Mower, J, Rafferty, MF, Herting, RL, Lanthorn, TH. Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention. Eur J Pharmacol. 1994;257:712.
40.Cammarota, M, Barros, DM, Vianna, MR, et al.The transition from memory retrieval to extinction. An Acad Bras Cienc. 2004;76:573582.
41.Krystal, JH, Sanacora, G, Blumberg, H, et al.Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002;7(suppl 1):S71S80.
42.Inanobe, A, Furukawa, H, Gouaux, E, et al.Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron. 2005;47:7184.
43.Fitzgerald, DA, Angstadt, M, Jelsone, LM, Nathan, PJ, Phan, KL. Beyond threat: amygdala reactivity across multiple expressions of facial affect. Neuroimage. 2006;30:14411448.
44.Breiter, HC, Etcoff, NL, Whalen, PJ. Response and habituation of the human amygdala during visual processing of facial expression. Neuron. 1996;17:875887.
45.van Berckel, BN, Lipsch, C, Gispen-de Wied, C. The partial NMDA agonist D-cycloserine stimulates LH secretion in healthy volunteers. Psychopharmacology (Berl). 1998;138:190197.


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