A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans

School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia.
Behaviour Research and Therapy (Impact Factor: 3.85). 05/2007; 45(4):663-72. DOI: 10.1016/j.brat.2006.07.005
Source: PubMed

ABSTRACT Previous research has shown that D-cycloserine (DCS) facilitates extinction of Pavlovian fear conditioning in rats and enhances exposure therapy in humans. The aim of this study was to test the effect of DCS on extinction of fear conditioning in humans. In three experiments, 238 participants were given either DCS (50 or 500 mg) or placebo 2-3 h before extinction training following a differential shock conditioning paradigm. Clear extinction and recovery (return of fear) effects were observed on both skin conductance and self-reported shock expectancy measures in three studies. DCS had no influence on these effects. The same pattern was observed when the analysis was restricted to aware participants or to good conditioners, when fear-relevant cues (pictures of snakes) were used as the conditioned stimuli, or when analysis was restricted to heightened snake-fearful participants. These results suggest that DCS may not enhance the extinction, or prevent the recovery, of learned fear in a differential Pavlovian conditioning paradigm in humans. Further experimental research is needed to better understand the mechanisms underlying the therapeutic effects of DCS.

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Available from: Mark R Dadds, Jul 13, 2015
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    • "Additionally, evidence for learning effects in human studies analogous to the animal studies above has been more inconsistent. Although there is evidence from clinical trials that d-cycloserine may accelerate the therapy of different anxiety disorders (reviewed in Hofmann et al, 2013), some experimental studies have not been able to replicated the basic fear extinction effects in humans (Guastella et al, 2007; Klumpers et al, 2012). Furthermore, clinical trials for alcohol or for cocaine use extinction have failed to find an enhancement by d-cycloserine (Kamboj et al, 2011, Price et al, 2013). "
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    ABSTRACT: N-methyl-D-aspartate (NMDA) receptors are known to fulfil crucial functions in many forms of learning and plasticity. More recently, biophysical models however have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.Neuropsychopharmacology accepted article preview online, 13 June 2014; doi:10.1038/npp.2014.144.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.144 · 8.68 Impact Factor
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    • "However, the additional beneficial effects of DCS are rather small when provided in combination with an effective treatment such as cognitive behavioral therapy (CBT; Siegmund et al., 2011) Thus, DCS is suggested to be exclusively indicated for treating severely impaired patients (Siegmund et al., 2011; Klumpers et al., 2012). Moreover, experimental conditioning studies in healthy volunteers failed to show benefits of DCS on extinction learning or extinction recall (Guastella et al., 2007; Klumpers et al., 2012) thereby contradicting the above mentioned animal results (e.g., Walker et al., 2002). A different strategy to improve fear extinction is to electrically stimulate prefrontal regions involved in extinction memory consolidation. "
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    ABSTRACT: The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).
    Frontiers in Behavioral Neuroscience 02/2014; 8:44. DOI:10.3389/fnbeh.2014.00044 · 4.16 Impact Factor
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    • "A previous study suggested that both DCS and VPA enhance extinction learning of human fear conditioning and simultaneously prevent new acquisition of fear conditioning through so-called " habituation learning " (Kuriyama et al., 2011a). Although DCS exhibited a similar effect on reinstatement in rats (Ledgerwood et al., 2004), the effects of DCS and VPA on extinction and habituation learning were robust when reinstatement stimuli were exposed, rather than during the extinction and habituation learning per se, in humans (Guastella et al., 2007; Kuriyama et al., 2011a). When these drugs are applied clinically during exposure therapy for anxiety disorders or PTSD, we do not require enhancement of acquisition learning but rather enhancement of extinction learning of the fear (Hofmann, 2008). "
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    ABSTRACT: The effectiveness of d-cycloserine (DCS), an N-methyl-d-aspartate glutamate receptor partial agonist, and valproic acid (VPA), a histone deacetylase inhibitor, in facilitating the extinction of fear-conditioned memory has been explored in humans and animals. Here, we confirmed whether DCS (100 mg) and VPA (400 mg) act in off-line learning processes during sleep or waking, for further clinical application to anxiety disorders and posttraumatic stress disorder (PTSD). We performed a randomized, blind, placebo-controlled clinical trial in 90 healthy adults. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. The extinction effect was observed not in simple recall after the extinction of coupled CS-US, but was observed in the post-re-exposure phase after unexpected re-exposure to reinstatement CS-US coupling. Newly acquired conditioned fear was also eliminated or habituated by DCS and VPA administration, in line with previous findings. Furthermore, VPA facilitated the off-line learning process of conditioned fear extinction and habituation during sleep, while DCS facilitated this process during waking. These novel findings suggest that DCS and VPA might enhance exposure-based cognitive therapy for anxiety disorders and PTSD by reducing the vulnerability to reinstatement and preventing relapses of fear-conditioned responses, and provide evidence for a peculiarity of the sleep-dependent off-line learning process for conditioned fear extinction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
    Neuropharmacology 01/2013; 64(1):424-31. DOI:10.1016/j.neuropharm.2012.07.045 · 4.82 Impact Factor
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