Effects Of D-cycloserine Research Articles

The potential effect of d-cycloserine on the development of anxiety during exposure sessions in patients with agoraphobia

IntroductionCombination of exposure therapy with d-cycloserine (DCS) in patients suffering from anxiety disorders yielded promising results regarding treatment outcomes. However, less is known about short-term effects of DCS during the treatment process, e. g. its potential influence on anxiety during exposure sessions. In this exploratory secondary analysis using data from a randomized, double-blind, placebo-controlled trial, we investigated longitudinal changes in anxiety during exposure in agoraphobic patients receiving DCS or placebo (PBO). Methods73 patients suffering from agoraphobia (with or without panic disorder) were treated with 12 sessions of individual cognitive behavioral therapy including three exposure sessions. Patients were given either PBO or 50mg of DCS after each successful exposure. Multilevel modeling was used to analyze changes in outcomes measured in subjective units of distress (SUDS) over three time points (i.e. the exposure sessions) in the two groups. ResultsWe observed a decline in several SUDS outcomes in the DCS group, namely initial anxiety, maximum anxiety during exposure and within-session habituation, while the PBO group mostly maintained similar levels of anxiety from session to session. Anxiety at the end of exposure appeared to be stable in the DCS group as well. DiscussionOur findings suggest potential short-term effects of DCS on anxiety during exposure. Long lasting and high degree of anxiety over exposure sessions is burdensome for the patients. Thus, modifications to reduce anxiety during exposure or to accelerate the learning process while maintaining the same treatment efficacy could be desirable. However, given the exploratory nature of the analyses, confirmatory studies testing the hypothesis of a decline of SUDS in agoraphobic patients are needed before confident conclusions can be made.

Probing cognitive flexibility in Shank2-deficient mice: Effects of D-cycloserine and NMDAR signaling hub dynamics

Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2-deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2-deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2-deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility.

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study.

Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonist d-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials. 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg d-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between d-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety. No difference between d-cycloserine and placebo groups was observed across the primary or secondary outcome measures. d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of d-cycloserine would not be worthwhile.

Assessment of the neuroprotective potential of d-cycloserine and l-serine in aluminum chloride-induced experimental models of Alzheimer's disease: In vivo and in vitro studies.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain accompanied by synaptic dysfunction and neurodegeneration. No effective treatment has been found to slow the progression of the disease. Therapeutic studies using experimental animal models have therefore become very important. Therefore, this study aimed to investigate the possible neuroprotective effect of D-cycloserine and L-serine against aluminum chloride (AlCl3)-induced AD in rats. Administration of AlCl3 for 28 days caused oxidative stress and neurodegeneration compared to the control group. In addition, we found that aluminum decreases α-secretase activity while increasing β-secretase and γ-secretase activities by molecular genetic analysis. D-cycloserine and L-serine application resulted in an improvement in neurodegeneration and oxidative damage caused by aluminum toxicity. It is believed that the results of this study will contribute to the synthesis of new compounds with improved potential against AlCl3-induced neurodegeneration, cognitive impairment, and drug development research.

The Effect of D-Cycloserine on Brain Processing of Breathlessness Over Pulmonary Rehabilitation - an Experimental Medicine Study

The Effect of D-Cycloserine on Brain Processing of Breathlessness Over Pulmonary Rehabilitation - an Experimental Medicine Study

An Evaluation of the Effects of D-Cycloserine on Operant Learning and Response Recovery

D-cycloserine (DCS) is a drug that has generated great interest for its association with improvements in both learning and memory. Few studies have evaluated the effect of DCS on learning, extinction, and response recovery in operant conditioning. The present study aimed to evaluate, over three experiments with rats, the effect of DCS on the spontaneous recovery of a simple operant, and on the resurgence of operant behavior. DCS was expected to strengthen the extinction, and that a decrease in spontaneous recovery and resurgence would also be observed. The results showed a faster extinction in the groups that received DCS during the extinction; however, no differences were observed in the recovery of the response. Based on the present results, it is not possible to conclude that DCS is a supportive drug for learning processes such as exposure therapy.

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD

Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo (b = −0.19, CI = −0.01 to −37, p = 0.042 and b = −0.25, CI = −08 to −0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS− SCR in the DCS group, compared to placebo, (b = −0.25, CI = 0.04 to −0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.

Effect of D-cycloserine on Postoperative Neuropathic Pain after Lumbar Discectomy

Effect of D-cycloserine on Postoperative Neuropathic Pain after Lumbar Discectomy

Effects of D-Cycloserine on the Primary Motor Cortex Excitability in Healthy Human Subjects: A Paired-Pulse-Tms Protocol

Paired-pulse transcranial magnetic stimulation (ppTMS) can probe the human primary motor cortex excitability. Short interstimulus intervals (ISI<5ms) between a subthreshold and a suprathreshold pulse cause short-term intracortical inhibition (SICI), whereas longer ISI causes intracortical facilitation (ICF). NMDA-receptor antagonists decrease ICF, a proxy for glutamatergic transmission, and increase ICI and cortical silent period (CSP), for GABAergic transmission. The effect of NMDA-receptor agonists (e.g.

Experimental Drugs for Panic Disorder: An Updated Systematic Review.

Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I–III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO2 panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.

The effectiveness and adverse effects of D-cycloserine compared with placebo on social and communication skills in individuals with autism spectrum disorder.

Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted. To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD. In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies.In addition,we contacted pharmaceutical companies, searched manufacturers' websites and sources ofreports of adverse events. SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD. Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review. We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted attwo sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment.The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reportedlow certainty evidence of little to no differencebetween the two groups for alloutcomes measured at one week post-treatment:social interactionimpairment (mean difference (MD) 3.61 (assessed with theSocial Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment(MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD(RR 0.97 (measured by the Clinical Global Impression-Improvementscale), 95% CI 0.49 to 1.93); andtolerability of D-cycloserine(RR 0.32 (assessed by thenumber of dropouts), 95% CI 0.01 to 7.68). AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.

Effect of D-Cycloserine on the Effect of Concentrated Exposure and Response Prevention in Difficult-to-Treat Obsessive-Compulsive Disorder

Evidence is lacking for viable treatment options for patients with difficult-to-treat obsessive-compulsive disorder (OCD). It has been suggested that D-cycloserine (DCS) could potentiate the effect of exposure and response prevention (ERP) treatment, but the hypothesis has not been tested among patients with difficult-to-treat OCD. To evaluate whether DCS potentiates the effect of concentrated ERP among patients with difficult-to-treat OCD. The study was a randomized placebo-controlled triple-masked study with a 12-month follow-up. Participants were adult outpatients with difficult-to-treat OCD. A total of 220 potential participants were referred, of whom 36 did not meet inclusion criteria and 21 declined to participate. Patients had either relapsed after (n = 100) or not responded to (n = 63) previous ERP treatment. A total of 9 specialized OCD teams within the public health care system in Norway participated, giving national coverage. An expert team of therapists from the coordinating site delivered treatment. Inclusion of patients started in January 2016 and ended in August 2017. Data analysis was conducted February to September 2019. All patients received individual, concentrated ERP treatment delivered during 4 consecutive days in a group setting (the Bergen 4-day treatment format) combined with 100 mg DCS, 250 mg DCS, or placebo. Change in symptoms of OCD and change in diagnostic status. Secondary outcomes measures included self-reported symptoms of OCD, anxiety, depression, and quality of life. The total sample of 163 patients had a mean (SD) age of 34.5 (10.9) years, and most were women (117 [71.8%]). They had experienced OCD for a mean (SD) of 16.2 (10.2) years. A total of 65 patients (39.9%) were randomized to receive 100 mg DCS, 67 (41.1%) to 250 mg of DCS, and 31 (19.0%) to placebo. Overall, 91 (56.5%) achieved remission at posttreatment, while 70 (47.9%) did so at the 12-month follow-up. There was no significant difference in remission rates among groups. There was a significant reduction in symptoms at 12 months, and within-group effect sizes ranged from 3.01 (95% CI, 2.38-3.63) for the group receiving 250 mg DCS to 3.49 (95% CI, 2.78-4.18) for the group receiving 100 mg DCS (all P < .001). However, there was no significant effect of treatment group compared with placebo in obsessive-compulsive symptoms (250 mg group at posttreatment: d = 0.33; 95% CI, -0.10 to 0.76; 100 mg group at posttreatment: d = 0.36; 95% CI, -0.08 to 0.79), symptoms of depression and anxiety (eg, Patient Health Questionnaire-9 score among 250 mg group at 12-month follow-up: d = 0.30; 95% CI, -0.17 to 0.76; Generalized Anxiety Disorder-7 score among 100 mg group at 12-month follow-up: d = 0.27; 95% CI, -0.19 to 0.73), and well-being (250 mg group: d = 0.10; 95% CI, -0.42 to 0.63; 100 mg group: d = 0.34; 95% CI, -0.19 to 0.86). No serious adverse effects were reported. In this study, DCS did not potentiate ERP treatment effect, but concentrated ERP treatment was associated with improvement. ClinicalTrials.gov identifier: NCT02656342.

The gut-microbiome as a target for the treatment of schizophrenia: A systematic review and meta-analysis of randomised controlled trials of add-on strategies

The gut-microbiome has been hypothesised as a novel potential target for intervention for schizophrenia.We tested this hypothesis with a systematic review and meta-analysis of studies investigating the efficacy and acceptability of add-on strategies known to affect the gut-microbiome for the treatment of schizophrenia.Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobials, pre/probiotics, and faecal transplant in schizophrenia. Primary outcomes were severity of negative symptoms and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index.We identified 28 eligible trials: 21 investigated antibiotics, 4 antimicrobials (Artemisinin, Artemether, and Sodium Benzoate), 3 pre/probiotics, none faecal transplant.Results showed no effect of D-Cycloserine (10 studies; SMD, −0.16; 95% CI −0.40, 0.08; P = .20; I2: 28.2%), Minocycline (7 studies; SMD: −0.35; 95% CI −0.70, 0.00; P = .05, I2:77.7%), other antibiotics (2 studies), probiotics alone (1 study), and Artemisinin (1 study) on negative symptoms of schizophrenia when compared to placebo. Limited evidence suggests efficacy on negative symptoms for Sodium benzoate (2 studies; SMD, −0.63; 95%CI −1.03, −0.23; P < .001; I2:0%), Artemether (1 study), and probiotics combined with Vitamin D (1 study) when compared to placebo. Acceptability of intervention was similar to placebo.Negative findings were mainly led by antibiotics trials, with paucity of evidence available on pre/probiotics. There is a need of expanding our knowledge on the clinical relevance of gut-microbiome-host interaction in psychosis before engaging in further trials.

Is there place for nutrition in the treatment of children with autism spectrum disorder?

Autism is a neurodevelopmental disorder associated with significant social and financial burden. In recent years there has been an increasing interest in the use of dietary interventions as a complementary therapeutic option for these patients. The aim of this systematic review is to provide literature data about the effect of specific dietary interventions on clinical aspects of children with autism. For this reason, a literature search was conducted using Pubmed as the medical database source. No year-of-publication restriction was placed. Prospective studies conducted in pediatric populations and evaluating changes in clinical aspects of autism were considered. Types of dietary interventions evaluated in these studies included amino acids, fatty acids, vitamins/minerals, as well as specific diets (free of gluten/casein, ketogenic). The underlying mechanism of action of nutritional interventions in this pediatric population mainly includes regulation of neurotransmitters levels, as well as modification of gut microbiota. More specifically, Ν-acetylcysteine was shown to exert a beneficial effect on symptoms of irritability. This beneficial effect could be attributed to its antiglutamergic and antioxidative properties. With regards to fatty acids, it is known that they are involved in dopamine and serotonin metabolism, while low values of fatty acids have been reported in serum of patients with various neuropsychiatric disorders. However, their administration in children with autism did not make any difference in terms of clinical aspects of the disease. On the other hand, available literature data about effect of D-cycloserine, dimethylglycine and vitamins/minerals was either few or controversial. In parallel, we were able to identify in literature clinical studies showing a beneficial effect of gluten/casein-free and ketogenic diet on clinical phenotype of autism. Finally, it should be highlighted that no moderate or serious adverse events were reported in any of the above nutritional interventions. In general, current literature data is encouraging. Nevertheless, more randomized clinical trials are needed to more clearly confirm the effect of specific dietary interventions on clinical aspects of autism.

A randomized, placebo-controlled laboratory study of the effects of D-cycloserine on sexual memory consolidation in women

Rationale and objectiveThe aim of this study was to investigate the possible facilitating effect of the partial NMDA receptor agonist D-cycloserine (DCS) on memory consolidation of conditioned sexual responses and to examine the capability of DCS to reduce context-specificity of learning.MethodsIn a randomized placebo-controlled double-blind trial, 50 healthy females were exposed to a differential conditioning procedure. Two pictures of a male abdomen were used as conditional stimuli (CSs), of which one (the CS+) was followed by the unconditional stimulus (US), a genital vibrotactile stimulus. After the conditioning session on day 1, participants received either 125 mg of DCS or a placebo. The effects of DCS on affect, sexual arousal and US expectancy in response to the CS+ and CS− were examined 24 h after the conditioning procedure.ResultsA main effect of DCS was found on affect at the first test trials (p = 0.04, ηp2 = 0.09), and a similar non-significant but trend level effect was found for sexual arousal (p = 0.06, ηp2 = 0.07), which appeared to persist over a longer time (p = 0.07, ηp2 = 0.08). Unexpectedly, ratings of positive affect and sexual arousal in response to both the CS+ and the CS− were higher in the DCS condition compared to the control condition, possibly indicating that DCS administration reduced stimulus specificity. Since the results did not show clear evidence for context learning, we were not able to test effects on context-specificity of learning.ConclusionAlthough largely inconclusive, the results provide tentative support for a facilitating effect of DCS on affect and sexual arousal in response to stimuli that were presented in a sexual conditioning procedure, however, no conclusions can be drawn about effects of DCS on sexual reward learning, since the design and results do not lend themselves to unambiguous interpretation.

Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D2/3R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D2/3R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.

The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model

BackgroundN-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo.MethodsBy using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice.ResultsIn vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice.ConclusionsWe conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder.

Preclinical and clinical data have shown that D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor complex, augments the retention of fear extinction in animals and the therapeutic learning from exposure therapy in humans. However, studies with non-clinical human samples in de novo fear conditioning paradigms have demonstrated minimal to no benefit of DCS. The aim of this study was to evaluate the effects of DCS on the retention of extinction learning following de novo fear conditioning in a clinical sample. Eighty-one patients with social anxiety disorder were recruited and underwent a previously validated de novo fear conditioning and extinction paradigm over the course of three days. Of those, only 43 (53%) provided analyzable data. During conditioning on Day 1, participants viewed images of differently colored lamps, two of which were followed by with electric shock (CS+) and a third which was not (CS-). On Day 2, participants were randomly assigned to receive either 50 mg DCS or placebo, administered in a double-blind manner 1 hour prior to extinction training with a single CS+ in a distinct context. Day 3 consisted of tests of extinction recall and renewal. The primary outcome was skin conductance response to conditioned stimuli, and shock expectancy ratings were examined as a secondary outcome. Results showed greater skin conductance and expectancy ratings in response to the CS+ compared to CS- at the end of conditioning. As expected, this difference was no longer present at the end of extinction training, but returned at early recall and renewal phases on Day 3, showing evidence of return of fear. In contrast to hypotheses, DCS had no moderating influence on skin conductance response or expectancy of shock during recall or renewal phases. We did not find evidence of an effect of DCS on the retention of extinction learning in humans in this fear conditioning and extinction paradigm.

Individual differences of rats and effects of d-Cycloserine on the acquisition of spatial memory

Individual differences of rats and effects of d-Cycloserine on the acquisition of spatial memory

The Effect of D-cycloserine on Emotional Processing

The Effect of D-cycloserine on Emotional Processing