Review| Volume 60, ISSUE 4, P369-375, August 15, 2006

Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work

      Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Baker J.D.
        • Azorlosa J.L.
        The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning.
        Behav Neurosci. 1996; 110: 618-620
        • Baxter M.
        • Lanthorn T.
        • Frick K.
        • Golski S.
        • Wan R.
        • Olton D.
        D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats.
        Neurobiol Aging. 1994; 15: 207-213
        • Bear M.F.
        A synaptic basis for memory storage in the cerebral cortex.
        Proc Natl Acad Sci U S A. 1996; 93: 13453-13459
        • Bisson J.I.
        • Jenkins P.L.
        • Alexander J.
        • Bannister C.
        Randomised controlled trial of psychological debriefing for victims of acute burn trauma.
        Br J Psychiatry. 1997; 171: 78-81
        • Bouton M.D.
        • Bolles R.C.
        Role of contextual stimuli in reinstatement of extinguished fear.
        J Exp Psychol Anim Behav Process. 1979; 5: 368-378
        • Bouton M.E.
        • Bolles R.C.
        Contextual control of the extinction of conditioned fear.
        Learning and Motivation. 1979; 10: 455-466
        • Bouton M.E.
        • Kenney F.A.
        • Rosengard C.
        State-dependent fear extinction with two benzodiazepine tranquilizers.
        Behav Neurosci. 1990; 104: 44-55
        • Castellano C.
        • Cestari V.
        • Ciamei A.
        NMDA receptors and learning and memory processes.
        Curr Drug Targets. 2001; 2: 273-283
        • Cox J.
        • Westbrook R.F.
        The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesia responses in the rat.
        Q J Exp Psychol. 1994; 47B: 187-210
        • Denniston J.C.
        • Chang R.C.
        • Miller R.R.
        Massive extinction treatment attenuates the renewal effect.
        Learning and Motivation. 2003; 34: 68-86
        • Fakouhi T.
        • Jhee S.
        • Sramek J.
        • Benes C.
        • Schwartz P.
        • Hantsburger G.
        • et al.
        Evaluation of cycloserine in the treatment of Alzheimer’s disease.
        J Geriatric Psych Neurol. 1995; 8: 226-230
        • Falls W.A.
        • Miserendino M.J.
        • Davis M.
        Extinction of fear-potentiated startle.
        J Neurosci. 1992; 12: 854-863
        • Hofmann S.G.
        • Meuret A.E.
        • Smits J.A.
        • Simon N.M.
        • Pollack M.H.
        • Eisenmenger K.
        • et al.
        Augmentation of exposure therapy with D-cycloserine for social anxiety disorder.
        Arch Gen Psychiatry. 2006; 63: 298-304
        • Kehoe E.J.
        • Macrae M.
        • Hutchinson C.L.
        MK-801 protects conditioned response from extinction in the rabbit nictitating membrane preparation.
        Psychobiology. 1996; 24: 127-135
        • Konorski J.
        Integrative Activity of the Brain. The University of Chicago Press, Chicago1967
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine facilitates extinction of conditioned fear as assessed by freezing in rats.
        Behav Neurosci. 2003; 117: 341-349
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine and reinstatement.
        Behav Neurosci. 2004; 118: 505-513
        • Ledgerwood L.
        • Richardson R.
        • Cranney J.
        D-cycloserine facilitates extinction of learned fear.
        Biol Psychiatry. 2005; 57: 841-847
        • Lee H.
        • Kim J.J.
        Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats.
        J Neurosci. 1998; 18: 8444-8454
        • Mayou R.A.
        • Ehlers A.
        • Hobbs M.
        Psychological debriefing for road traffic accident victims. Three-year follow-up of a randomised controlled trial.
        Br J Psychiatry. 2000; 176: 589-593
        • Miserendino M.J.
        • Sananes C.B.
        • Melia K.R.
        • Davis M.
        Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala.
        Nature. 1990; 345: 716-718
        • Morris R.G.
        • Davis S.
        • Butcher S.P.
        Hippocampal synaptic plasticity and NMDA receptors.
        Philos Trans R Soc Lond B Biol Sci. 1990; 329: 187-204
        • Myers K.M.
        • Davis M.
        Behavioral and neural analysis of extinction.
        Neuron. 2002; 36: 567-584
        • Newcomer J.W.
        • Krystal J.H.
        NMDA receptor regulation of memory and behavior in humans.
        Hippocampus. 2001; 11: 529-542
        • Parnas A.S.
        • 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
        • Pavlov I.P.
        Conditioned Reflexes. Oxford University Press, Oxford, United Kingdom1927
        • Quartermain D.
        • Mower J.
        • Rafferty M.
        • Herting R.
        • Lanthorn T.
        Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention.
        Eur J Pharmacol. 1994; 257: 7-12
        • Randolph C.
        • Roberts J.
        • Tierney M.
        • Bravi D.
        • Mourandian M.
        • Chase T.
        D-cycloserine treatment of Alzheimer’s disease.
        Alzheimers Dis Assoc Disord. 1994; 8: 198-205
        • Rescorla R.A.
        • Heth C.D.
        Reinstatement of fear to an extinguished conditioned stimulus.
        J Exp Psychol Anim Behav Processes. 1975; 1: 88-96
        • Ressler K.J.
        • Rothbaum B.O.
        • Tannenbaum L.
        • et al.
        Cognitive enhancers as adjuncts to psychotherapy.
        Arch Gen Psychiatry. 2004; 61: 1136-1144
        • Richardson R.
        • Ledgerwood L.
        • Cranney J.
        Facilitation of fear extinction by D-cycloserine.
        Learn Mem. 2004; 11: 510-516
        • Rothbaum B.O.
        • Hodges L.
        • Smith S.
        • Lee J.H.
        • Price L.
        A controlled study of virtual reality exposure therapy for the fear of flying.
        J Consult Clin Psychol. 2000; 68: 1020-1026
        • Rothbaum B.O.
        • Hodges L.F.
        • Kooper R.
        • Opdyke D.
        • Williford J.S.
        • North M.
        Effectiveness of computer-generated (virtual reality) graded exposure in the treatment of acrophobia.
        Am J Psychiatry. 1995; 152: 626-628
        • Rothbaum B.O.
        • Hodges L.F.
        • Ready D.
        • Graap K.
        • Alarcon R.D.
        Virtual reality exposure therapy for Vietnam veterans with posttraumatic stress disorder.
        J Clin Psychiatry. 2001; 62: 617-622
        • Santini E.
        • Muller R.U.
        • Quirk G.J.
        Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory.
        J Neurosci. 2001; 21: 9009-9017
        • Schuster G.M.
        • Schmidt W.J.
        D-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task.
        Eur J Pharmacol. 1992; 224: 97-98
        • Schwartz B.L.
        • Hashtroudi S.
        • Herting R.L.
        • Schwartz P.
        • Deutsch S.I.
        d-Cycloserine enhances implicit memory in Alzheimer patients.
        Neurology. 1996; 46: 420-424
        • Szapiro G.
        • Vianna M.R.
        • McGaugh J.L.
        • Medina J.H.
        • Izquierdo I.
        The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear.
        Hippocampus. 2003; 13: 53-58
        • Thompson L.T.
        • Moskal J.R.
        • Disterhoft J.F.
        Hippocampus-dependent learning facilitated by a monoclonal antibody or D-cycloserine.
        Nature. 1992; 359: 638-641
        • Tsai G.
        • Falk W.
        • Gunther J.
        A preliminary study of D-cycloserine treatment in Alzheimer’s disease.
        J Neuropsychiatry Clin Neurosci. 1998; 10: 224-226
        • Walker D.L.
        • Ressler K.J.
        • Lu K.-T.
        • 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
        • Yang Y.L.
        • Lu T.
        Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala.
        Neuroscience. 2005; 134: 247-260