Elsevier

Biological Psychiatry

Volume 60, Issue 4, 15 August 2006, Pages 369-375
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2006.03.084Get rights and content

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.

Section snippets

The Role of N-Methyl-D-Aspartate Receptors in Extinction

Extinction typically does not result from an erasure of the original fear memory but instead represents a new form of learning that acts to inhibit or suppress the original fear memory (Bouton and Bolles 1979a, Konorski 1967, Pavlov 1927). A large body of literature suggests that glutamate acting at the N-methyl-D-aspartate (NMDA) receptor is critically involved in learning and memory (Bear 1996, Castellano et al 2001, Morris et al 1990, Newcomer and Krystal 2001). For example, Miserendino et

Facilitation of Extinction With an NMDA Partial Agonist

Because the blockade of the NMDA receptor impairs extinction, it was logical to wonder if enhancing the functioning of that receptor would enhance extinction. To test this we administered a compound called D-cycloserine (DCS) either systemically or directly into the rats’ amygdala before extinction training and then tested retention of extinction the next day (Walker et al 2002). D-cycloserine does not bind to the NMDA receptor itself but to another receptor on the NMDA protein called the

Does DCS Cause “Generalized” Extinction?

Perhaps the most surprising result from the recent preclinical studies on DCS and extinction is that DCS seems to lead to generalized extinction (Ledgerwood et al 2005). In that study, rats were initially trained with two different cues (i.e., a light and a tone), each paired with a loud aversive noise. The next day some rats were given two sessions (separated by 2 hours) of extinction training with the visual cue (six non-reinforced exposures to the 2-min light in each session). Immediately

DCS Reduces Reinstatement of Learned Fear After Extinction

In another study, Ledgerwood et al (2004) found that DCS might block relapse (i.e., a return of the learned fear response) that normally occurs when extinction training is followed by a stress, a phenomenon referred to as reinstatement. In that study, rats were first trained to be afraid of a light by pairing it with a footshock and then, the next day, given extinction training followed by injection of either DCS or saline. To equate levels of fear before stress, the saline-treated rats were

DCS Does Not Seem to Facilitate Fear Conditioning and Might Even Reduce It

If DCS is so effective in facilitating learning, then one might wonder whether it could actually be harmful if combined with exposure-based psychotherapy. For example, bringing to mind awful memories of a traumatic event can lead to sensitization rather than extinction if a full therapeutic exposure is not carried out (Bisson et al 1997, Mayou et al 2000). Perhaps sensitization would be exacerbated by DCS by reinstantiating the fearful memories. Thus far none of us have seen any evidence of

A Clinical Test of Combining DCS With Behavioral Exposure Therapy for Acrophobia

Recently we tested whether DCS given in combination with exposure therapy for the treatment of specific phobia in humans would improve the effectiveness of this therapy (Ressler et al 2004). We wished to examine the ability of DCS to enhance exposure therapy in humans with the most optimally controlled form of psychotherapeutic learning available. Virtual reality exposure (VRE) therapy is ideal for clinical research assessment because exposure and testing is identical between patients, is well

References (42)

  • J.I. Bisson et al.

    Randomised controlled trial of psychological debriefing for victims of acute burn trauma

    Br J Psychiatry

    (1997)
  • M.D. Bouton et al.

    Role of contextual stimuli in reinstatement of extinguished fear

    J Exp Psychol Anim Behav Process

    (1979)
  • M.E. Bouton et al.

    Contextual control of the extinction of conditioned fear

    Learning and Motivation

    (1979)
  • M.E. Bouton et al.

    State-dependent fear extinction with two benzodiazepine tranquilizers

    Behav Neurosci

    (1990)
  • C. Castellano et al.

    NMDA receptors and learning and memory processes

    Curr Drug Targets

    (2001)
  • J. Cox et al.

    The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesia responses in the rat

    Q J Exp Psychol

    (1994)
  • T. Fakouhi et al.

    Evaluation of cycloserine in the treatment of Alzheimer’s disease

    J Geriatric Psych Neurol

    (1995)
  • W.A. Falls et al.

    Extinction of fear-potentiated startleBlockade by infusion of an NMDA antagonist into the amygdala

    J Neurosci

    (1992)
  • S.G. Hofmann et al.

    Augmentation of exposure therapy with D-cycloserine for social anxiety disorder

    Arch Gen Psychiatry

    (2006)
  • E.J. Kehoe et al.

    MK-801 protects conditioned response from extinction in the rabbit nictitating membrane preparation

    Psychobiology

    (1996)
  • J. Konorski

    Integrative Activity of the BrainAn Interdisciplinary Approach

    (1967)
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