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


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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    • "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.
    Full-text · Article · Jun 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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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).
    Full-text · Article · Feb 2014 · Frontiers in Behavioral Neuroscience
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    • "Small molecules targeting these brakes carry potential clinical relevance for both neurological and psychiatric disease, including PTSD. It is well-established that administering d-cycloserine (DCS), a partial NMDA agonist, facilitates extinction, and prevents the recovery of fear memories in rats, mice, and humans both before and after extinction training (46–49). Here we discuss the possibility of additionally using three well-established drug classes administered in humans – selective serotonergic reuptake inhibitors (SSRIs), acetylcholinesterase inhibitors (AChEIs), and histone deacetylase (HDAC) inhibitors – to target both structural and functional plasticity brakes based on data from both animal and human studies (Figure 1C). "
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    ABSTRACT: Early temporary windows of heightened brain plasticity called critical periods developmentally sculpt neural circuits and contribute to adult behavior. Regulatory mechanisms of visual cortex development - the preeminent model of experience-dependent critical period plasticity-actively limit adult plasticity and have proved fruitful therapeutic targets to reopen plasticity and rewire faulty visual system connections later in life. Interestingly, these molecular mechanisms have been implicated in the regulation of plasticity in other functions beyond vision. Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder. In this review, we turn to the model of experience-dependent visual plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system. Fear circuitry, particularly fear memory erasure, also undergoes age-related changes in experience-dependent plasticity. We consider the contributions of molecular brakes that halt visual critical period plasticity to circuitry underlying fear memory erasure. A major molecular brake in the visual cortex, perineuronal net formation, recently has been identified in the development of fear systems that are resilient to fear memory erasure. The roles of other molecular brakes, myelin-related Nogo receptor signaling and Lynx family proteins - endogenous inhibitors for nicotinic acetylcholine receptor, are explored in the context of fear memory plasticity. Such fear plasticity regulators, including epigenetic effects, provide promising targets for therapeutic interventions.
    Full-text · Article · Nov 2013 · Frontiers in Psychiatry
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