Administration Of D-cycloserine Research Articles

Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats.

Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.

Homeostatic Synaptic Plasticity may be Targeted for the Prevention of Post-Stroke Epilepsy

Stroke is the most common cause of acquired epilepsy, with up to 30 percent of stroke survivors developing epilepsy over time. However, the mechanisms leading to neuronal hyperexcitability and epilepsy in stroke survivors are not fully understood. In a recently published work, we demonstrate that ischemic stroke induces homeostatic plasticity regulation in the surviving neurons in the peri-stroke area. Furthermore, activity enhancement through optogenetic stimulation of excitatory pyramidal neurons in the peri-stroke area or systemic administration of D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, reduces seizure susceptibility in mice. Here, we briefly review current understanding on the role of homeostatic plasticity in post-stroke epileptogenesis and discuss how homeostatic plasticity could be targeted to prevent post-stroke epilepsy. We comment on our activity enhancement findings and close by discussing implications for clinical treatment.

Preventing development of post-stroke hyperexcitability by optogenetic or pharmacological stimulation of cortical excitatory activity

Stroke is the most common cause of acquired epilepsy, but treatment for preventing the development of post-stroke epilepsy is still unavailable. Since stroke results in neuronal damage and death as well as initial loss of activity in the affected brain region, homeostatic plasticity may be trigged and contribute to an increase in network hyperexcitability that underlies epileptogenesis. Correspondingly, enhancing brain activity may inhibit hyperexcitability from enhanced homeostatic plasticity and prevent post-stroke epileptogenesis. To test these hypotheses, we first used in vivo two-photon and mesoscopic imaging of activity of cortical pyramidal neurons in Thy1-GCaMP6 transgenic mice to determine longitudinal changes in excitatory activity after a photothrombotic ischemic stroke. At 3-days post-stroke, there was a significant loss of neuronal activity in the peri-injury area as indicated by reductions in the frequency of calcium spikes and percentage of active neurons, which recovered to baseline level at day 7, supporting a homeostatic activity regulation of the surviving neurons in the peri-injury area. We further used optogenetic stimulation to specifically stimulate activity of pyramidal neurons in the peri-injury area of Thy-1 channelrhodopsin transgenic mice from day 5 to day 15 after stroke. Using pentylenetetrazole test to evaluate seizure susceptibility, we showed that stroke mice are more susceptible to Racine stage V seizures (time latency 54.3 ± 12.9 min) compared to sham mice (107.1 ± 13.6 min), but optogenetic stimulation reversed the increase in seizure susceptibility (114.0 ± 9.2 min) in mice with stroke. Similarly, administration of D-cycloserine, a partial N-methyl-d-aspartate (NMDA) receptor agonist that can mildly enhance neuronal activity without causing post-stroke seizure, from day 5 to day 15 after a stroke significantly reversed the increase in seizure susceptibility. The treatment also resulted in an increased survival of glutamic acid decarboxylase 67 (GAD67) positive interneurons and a reduced activation of glial fibrillary acidic protein (GFAP) positive reactive astrocytes. Thus, this study supports the involvement of homeostatic activity regulation in the development of post-stroke hyperexcitability and potential application of activity enhancement as a novel strategy to prevent post-stroke late-onset seizure and epilepsy through regulating cortical homeostatic plasticity.

Practice makes plasticity: 10-Hz rTMS enhances LTP-like plasticity in musicians and athletes.

Motor skill learning has been linked to functional and structural changes in the brain. Musicians and athletes undergo intensive motor training through the practice of an instrument or sport and have demonstrated use-dependent plasticity that may be subserved by long-term potentiation (LTP) processes. We know less, however, about whether the brains of musicians and athletes respond to plasticity-inducing interventions, such as repetitive transcranial magnetic stimulation (rTMS), differently than those without extensive motor training. In a pharmaco-rTMS study, we evaluated motor cortex excitability before and after an rTMS protocol in combination with oral administration of D-cycloserine (DCS) or placebo. In a secondary covariate analysis, we compared results between self-identified musicians and athletes (M&As) and non-musicians and athletes (non-M&As). Three TMS measures of cortical physiology were used to evaluate plasticity. We found that M&As did not have higher baseline corticomotor excitability. However, a plasticity-inducing protocol (10-Hz rTMS in combination with DCS) strongly facilitated motor-evoked potentials (MEPs) in M&As, but only weakly in non-M&As. Placebo and rTMS produced modest facilitation in both groups. Our findings suggest that motor practice and learning create a neuronal environment more responsive to plasticity-inducing events, including rTMS. These findings may explain one factor contributing to the high inter-individual variability found with MEP data. Greater capacity for plasticity holds implications for learning paradigms, such as psychotherapy and rehabilitation, by facilitating LTP-like activation of key networks, including recovery from neurological/mental disorders.

NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice.

Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spectrum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social deficits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-positive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunction in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.

Synergistic enhancing-memory effect of D-serine and RU360, a mitochondrial calcium uniporter blocker in rat model of Alzheimer's disease

BackgroundAlthough Amyloid beta (Aβ) and N - methyl d- aspartate receptors (NMDARs are involved in Ca2+ neurotoxicity, the function of mitochondrial calcium uniporter in cognition deficit remain uncertain. Here, we examined the effect of mitochondrial calcium uniporter (MCU) blocker, together with NMDA receptor agonist d-cycloserine (DCS) on memory impairment in a rat model of AD. MethodsForty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intracerebroventricular (ICV) injection of Aβ1–42 (5 μg /8 μl/rat). Then animals were divided into 5 groups of: Saline + Saline, Aβ + Saline, Aβ + RU360, Aβ + DCS, Aβ + RU360 + DCS. Two weeks after the treatments, Morris Water Maze (MWM) and step through passive avoidance learning (SPL) were undertaken for evaluating of spatial and associative memories, respectively. Hippocampal level of cyclic-AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were measured by western blot and ELISA. ResultsCo - administration of RU360 and DCS significantly improved both acquisition and retrieval of spatial memory as evident by decreased escape latency and increased time spent in the target quadrant (TTS) in MWM, together with increase in step-through latency, but reduced time spent in the dark compartment in SPL. Furthermore, there was a significant rise in the hippocampal level of CREB and BDNF in comparison with Aβ + Saline. ConclusionThe present study supports the idea that co- administration of RU360 and DCS ameliorate memory impairment induced by Aβ 1–42 probably via CREB / BDNF signaling.

Dose Timing of D-Cycloserine to Augment Exposure Therapy for Social Anxiety Disorder

Findings suggest that the efficacy of D-cycloserine (DCS) for enhancing exposure therapy may be strongest when administered after sessions marked by low fear at the conclusion of exposure practice. These findings have prompted investigation of DCS dosing tailored to results of exposure sessions. To compare tailored postsession DCS administration with presession DCS administration, postsession DCS administration, and placebo augmentation of exposure therapy for social anxiety disorder. This double-blind randomized clinical trial involved adults with social anxiety disorder enrolled at 3 US university centers. Symptom severity was assessed at baseline, weekly during treatment, and at 1-week and 3-month follow-up. Data analysis was performed from September 2019 to March 2020. Participants completed a 5-session treatment and received pills commensurate with their condition assignment at sessions 2 through 5, which emphasized exposure practice. Symptom severity was evaluated by the Liebowitz Social Anxiety Scale and Social Phobic Disorders-Severity Form as administered by independent evaluators. A total of 152 participants were enrolled (mean [SD] age, 29.24 [10.16] years; 84 men [55.26%]). Compared with placebo, presession and postsession conditions showed greater symptom improvement (b = -0.25; 95% CI, -0.37 to -0.13; P < .001; d = 1.07; and b = -0.20; 95% CI, -0.32 to -0.07; P = .002; d = 0.85) and lower symptom severity (b = -0.51; 95% CI, -0.81 to -0.21; P < .001; d = 0.76; and b = -0.49; 95% CI, -0.80 to -0.18; P = .002; d = 0.72) at 3-month follow-up. No differences were found between presession and postsession conditions. The tailored condition showed no advantage over placebo. Compared with the tailored condition, presession and postsession conditions evidenced greater decreases (b = -0.22; 95% CI, -0.34 to -0.10; P < .001; d = 0.94; and b = -0.17, 95% CI, -0.29 to -0.04; P = .008; d = 0.72) and lower symptom severity (b = -0.44, 95% CI, -0.73 to -0.14; P = .004; d = 0.64; and b = -0.41, 95% CI, -0.72 to -0.11; P = .008; d = 0.61) at 3-month follow-up. Administration of DCS enhanced exposure therapy for social anxiety disorder when given before or after the exposure session. However, the study failed to achieve the aim to develop a tailored clinical application. ClinicalTrials.gov Identifier: NCT02066792.

CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors

Synaptic dysregulation is a critical feature of autism spectrum disorders (ASDs). Among various autism-associated genes, cortactin binding protein 2 (CTTNBP2) is a cytoskeleton regulator predominantly expressed in neurons and highly enriched at dendritic spines. Here, using Cttnbp2 knockout and ASD-linked mutant mice, we demonstrate that Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs dendritic spine formation and ultrastructure of postsynaptic density, and influences neuronal activation and autism-like behaviors. A link to autism, the NMDAR-SHANK pathway, and zinc-related regulation are three features shared by CTTNBP2-regulated synaptic proteins. Zinc supplementation rescues the synaptic expression of CTTNBP2-regulated proteins. Moreover, zinc supplementation and administration of D-cycloserine, an NMDAR coagonist, improve the social behaviors of Cttnbp2-deficient mice. We suggest that CTTNBP2 controls the synaptic expression of a set of zinc-regulated autism-associated genes and influences NMDAR function and signaling, providing an example of how genetic and environmental factor crosstalk controls social behaviors.

Glutamatergic Contribution to Probabilistic Reasoning and Jumping to Conclusions in Schizophrenia: A Double-Blind, Randomized Experimental Trial

BackgroundImpaired probabilistic reasoning and the jumping-to-conclusions reasoning bias are hallmark features of schizophrenia (SCZ), yet the neuropharmacological basis of these deficits remains unclear. Here we tested the hypothesis that glutamatergic neurotransmission specifically contributes to jumping to conclusions and impaired probabilistic reasoning in SCZ. MethodsA total of 192 healthy participants received either NMDA receptor agonists/antagonists (D-cycloserine/dextromethorphan), dopamine type 2 receptor agonists/antagonists (bromocriptine/haloperidol), or placebo in a randomized, double-blind, between-subjects design. In addition, we tested 32 healthy control participants matched to 32 psychotic inpatients with SCZ—a state associated with compromised probabilistic reasoning due to reduced glutamatergic neurotransmission. All experiments employed two versions of a probabilistic reasoning (beads) task, which required participants to either sample individual amounts of sensory information to infer correct decisions or provide explicit probability estimates for presented sensory information. Our task instantiations assessed both information sampling and explicit probability estimates in different probabilistic contexts (easy vs. difficult conditions) and changing sensory information through random transitions among easy, difficult, and ambiguous trial types. ResultsFollowing administration of D-cycloserine, haloperidol, and bromocriptine, healthy participants displayed data-gathering behavior that was normal compared with placebo and was adequate in the context of all employed task conditions and trial level difficulties. However, healthy participants receiving dextromethorphan displayed a jumping-to-conclusions bias, abnormally increased probability estimates, and overweighting of sensory information. These effects were mirrored in patients with SCZ performing the same versions of the beads task. ConclusionsOur findings provide novel neuropharmacological evidence linking reduced glutamatergic neurotransmission to impaired information sampling and to disrupted probabilistic reasoning, namely to overweighting of sensory evidence, in patients with SCZ.

Randomized controlled trial of d-cycloserine in cocaine dependence: Effects on contingency management and cue-induced cocaine craving in a naturalistic setting.

Cocaine dependence constitutes a significant public health concern. This randomized, double-blind, placebo-controlled trial tested a novel approach to reducing cocaine use among cocaine-dependent individuals with d-cycloserine, a drug known to enhance learning and some learning-based therapies. Urine samples and cocaine craving were assessed across three phases: induction (Weeks 1-2), treatment (Weeks 3-5; urinalysis-based contingency management plus exposure therapy), and posttreatment (Weeks 6-7). During the treatment phase, either 50 mg of d-cycloserine or placebo was administered after delivery of urinalysis feedback with potential monetary reward and before exposure therapy sessions in naturalistic contexts individually associated with cocaine use. d-cycloserine significantly improved learning on an operant laboratory task. Contingency management significantly reduced cocaine use and craving. d-cycloserine did not significantly affect cocaine use or craving in the treatment phase. Craving significantly increased for the d-cycloserine group during the post treatment phase. Therefore, although the study showed that d-cycloserine was capable of improving learning, enhancement of learning-based therapy was not observed. Moreover, no differences in behavioral measures of cocaine demand (cocaine purchasing task) or monetary or sexual delay discounting were observed across phases or between groups in any phase. These results are somewhat consistent with previous findings suggesting that d-cycloserine administration increases cocaine craving, although they differ from other findings showing that d-cycloserine administration reduces alcohol or nicotine cravings. Methodological variables (e.g., guided vs. unguided exposure therapy sessions, length of extinction exposure) likely play a role in dissimilar findings observed across studies. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Anterior Commissure Regulates Neuronal Activity of Amygdalae and Influences Locomotor Activity, Social Interaction and Fear Memory in Mice.

The two hemispheres of the vertebrate brain are connected through several commissures. Although the anterior commissure (AC) is the most conserved white matter structure in the brains of different vertebrates, its complete physiological functionality remains elusive. Since the AC is involved in the connection between two amygdalae and because amygdalae are critical for emotional behaviors and social interaction, we assessed amygdalar activity and function to investigate the physiological role of the AC. We first performed ex vivo electrophysiological recording on mouse brains to demonstrate that the AC delivers a positive signal to facilitate synaptic responses and to recruit basolateral amygdalar neurons via glutamatergic synapses. Transection was then undertaken to investigate the role of the AC in vivo. Results from in vivo optogenetic stimulation suggest that AC transection impairs mutual activation between two basolateral amygdalae. Behavioral analyses were then used to assess if AC surgical lesioning results in hyperactivity, anxiety, social reduction or learning/memory impairment, which are behavioral features associated with neuropsychiatric disorders, such as autism spectrum disorders. We found that AC transection results in higher locomotor activity, aberrant social interaction and reduced associative memory, but not anxiety. Moreover, systemic administration of D-cycloserine, a coagonist of N-methyl-D-aspartate receptor, ameliorated auditory fear memory in AC-transected mice, reinforcing our evidence that the AC potentiates the activity of basolateral amygdalae. Our study suggests that the AC regulates basolateral amygdalar activity and influences neuropsychiatry-related behaviors in mice.

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.

D-cycloserine as adjunct to brief computerised CBT for spider fear: Effects on fear, behaviour, and cognitive biases

Background and objectivesIn anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). MethodsSpider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up. ResultsLinear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses. LimitationsResults might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects. ConclusionsThese findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS.

Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

D-Cycloserine and estradiol enhance fear extinction in nulliparous but not primiparous female rats

Female reproductive experience has been shown to alter the hormonal, neurobiological and behavioural features of fear extinction, which is the laboratory basis of exposure therapy. This raises uncertainties as to whether pharmacological agents that enhance fear extinction in reproductively inexperienced females are equally effective in reproductively experienced females. The aim of the current study was therefore to compare the effects of two pharmacological enhancers of fear extinction, d-cycloserine (DCS) and estradiol, between nulliparous (virgin) and primiparous (reproductively experienced) female rats. In Experiment 1, nulliparous and primiparous females received systemic administration of either DCS or saline immediately after extinction training, and were tested for extinction recall the following day. DCS enhanced extinction recall in nulliparous females that showed low levels of freezing at the end of extinction training, but not among those that showed high levels of freezing at the end of extinction training. DCS did not enhance fear extinction in primiparous females, regardless of their level of freezing at the end of extinction training. In Experiment 2, nulliparous and primiparous female rats received systemic administration of either estradiol or vehicle prior to extinction training. Estradiol enhanced extinction recall among nulliparous females, but not primiparous females. Increasing the dose of estradiol administered prior to extinction training did not alter the outcomes in primiparous females (Experiment 3). Together, these findings suggest that reproductive status may be an important individual difference factor associated with the response to pharmacological modulators of extinction in rats. The implications of these findings for the pharmacological augmentation of exposure therapy in clinical populations are discussed.

Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice

BackgroundAutism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice.MethodsWe used Tbr1+/− mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1+/− mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation.ResultsTbr1+/− mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1+/− olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1+/− mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1+/− mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency.ConclusionsTbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1+/− mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.

Learn to forget: Does post-exposure administration of d-cycloserine enhance fear extinction in agoraphobia?

The use of d-cycloserine (DCS) to augment exposure based therapy for anxiety disorders has shown mixed, although overall positive effects. Aim of the present study was to examine post-exposure administration of DCS in patients with agoraphobia with or without panic disorder. 73 patients with agoraphobia (with or without panic disorder) were treated with 12 sessions of cognitive behavioral therapy (CBT) including 3 exposures. Following successful exposure patients were given double blind either placebo or 50 mg of DCS. Primary outcome criterion was change in the Panic and Agoraphobia Scale (PAS) between CBT session t1, t4 (+∼2 months), t10 (+∼3 months) und t11 (+∼4 months). During the course of CBT the patients' symptomatology decreased significantly as measured by primary and secondary outcome criteria, however, without an additional benefit for DCS treated patients. Exploratory sub-group analyses for severely ill patients and patients with high anxiety and strong habituation during exposure showed that DCS administration was associated with increased improvement during the 1-month follow-up period (t10 - t11) with medium to large effect sizes (range in effect size η2p from .06 to .25). Our study results are consistent with recent research on DCS, indicating a beneficial augmentative effect for sub-groups of anxiety patients. The lack of an overall DCS effect for the whole patient sample might be explained by a dual mechanism in fear conditioning and extinction with different cognitive processes being involved during exposure depending on the degree of anxiety experienced by the patient.

Estradiol-induced enhancement of fear extinction in female rats: The role of NMDA receptor activation

Converging cross-species evidence indicates that fear extinction (the laboratory basis of exposure therapy for anxiety disorders) in females is modulated by endogenous and exogenous estradiol. The mechanisms underlying estradiol's influences on fear extinction are largely undefined. However, one likely candidate is the NMDA-receptor (NMDAr), activation of which is necessary for estradiol-mediated enhancements in structural and functional neural plasticity, as well as extinction consolidation in males. Here, we demonstrate that systemic co-administration of the non-competitive NMDAr antagonist, MK801, blocked the enhancement of fear extinction by systemic estradiol in ovariectomized rats. In intact rats, MK801 during diestrus (rising estradiol) prevented the enhancement in extinction recall in rats that received extinction training during proestrus (peak estradiol). Systemic administration of the partial NMDAr agonist D-cycloserine (DCS) prior to extinction training facilitated extinction in ovariectomized rats, mimicking the effects of estradiol. In intact rats, DCS administered on the afternoon of proestrus and the morning of estrus (declining estradiol) facilitated extinction in rats that received extinction training during metestrus (low estradiol). Finally, DCS also facilitated extinction in ovariectomized rats when administered immediately after extinction training. Combined, these findings suggest that endogenous and exogenous estradiol enhance fear extinction via NMDAr-dependent mechanisms. Moreover, these findings raise the possibility that fear extinction deficits during periods of low endogenous estradiol levels can be reversed by increasing NMDAr activation via DCS administration, either well prior to, or immediately after, extinction training.

No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia: A Double-Blind, Randomized Controlled Trial.

D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the effectiveness of adding 125 mg of DCS to exposure therapy (before or directly after the first 6 treatment sessions) in patients with panic disorder with agoraphobia and (2) the effectiveness of DCS augmentation preceding exposure relative to DCS augmentation directly postexposure. Fifty-seven patients were allocated to 1 of 3 medication conditions (placebo and pre-exposure and postexposure DCS) as an addition to 6 exposure sessions within a 12-session exposure and response prevention protocol. The primary outcome measure was the mean score on the "alone" subscale of the Mobility Inventory (MI). No differences were found in treatment outcome between DCS and placebo, administered either pre-exposure or postexposure therapy, although at 3-month follow-up, the DCS postexposure group compared with DCS pre-exposure, exhibited greater symptom reduction on the MI-alone subscale. Ancillary analyses in specific subgroups (responders vs nonresponders, early vs late responders, severely vs mildly affected patients) did not reveal any between-group DCS versus placebo differences. Finally, the study did not find an effect of DCS relative to placebo to be specific for successful exposure sessions. This study does not find an effect of augmentation with DCS in patients with severe panic disorder and agoraphobia administered either pretreatment or directly posttreatment sessions. Moreover, no preferential effects are revealed in specific subgroups nor in successful exposure sessions. Yet, a small effect of DCS administration postexposure therapy cannot be ruled out, given the relatively small sample size of this study.