Receptor Partial Agonist D-cycloserine Research Articles

Human perceptual learning is delayed by the N-methyl-D-aspartate receptor partial agonist D-cycloserine.

Background:The optimisation of learning has long been a focus of scientific research, particularly in relation to improving psychological treatment and recovery of brain function. Previously, partial N-methyl-D-aspartate agonists have been shown to augment reward learning, procedural learning and psychological therapy, but many studies also report no impact of these compounds on the same processes.Aims:Here we investigate whether administration of an N-methyl-D-aspartate partial agonist (D-cycloserine) modulates a previously unexplored process – tactile perceptual learning. Further, we use a longitudinal design to investigate whether N-methyl-D-aspartate-related learning effects vary with time, thereby providing a potentially simple explanation for apparent mixed effects in previous research.Methods:Thirty-four volunteers were randomised to receive one dose of 250 mg D-cycloserine or placebo 2 h before tactile sensitivity training. Tactile perception was measured using psychophysical methods before and after training, and 24/48 h later.Results:The placebo group showed immediate within-day tactile perception gains, but no further improvements between-days. In contrast, tactile perception remained at baseline on day one in the D-cycloserine group (no within-day learning), but showed significant overnight gains on day two. Both groups were equivalent in tactile perception by the final testing – indicating N-methyl-D-aspartate effects changed the timing, but not the overall amount of tactile learning.Conclusions:In sum, we provide first evidence for modulation of perceptual learning by administration of a partial N-methyl-D-aspartate agonist. Resolving how the effects of such compounds become apparent over time will assist the optimisation of testing schedules, and may help resolve discrepancies across the learning and cognition domains.

D-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist d-cycloserine (DCS) improves extinction retention in adolescent rats. We investigated whether DCS affected recruitment of the PFC and amygdala during extinction by measuring pMAPK-immunoreactive (IR) neurons. Adolescent rats were trained to fear a conditioned stimulus in one context followed by extinction in a second context or equivalent context exposure only (i.e., no extinction). DCS (15 mg/kg, s.c.) or saline was administered systemically immediately after extinction training or context exposure. DCS enhanced extinction learning and this was associated with increased activation of the MAPK signaling pathway in the OFC after extinction training and increased activation in the medial PFC and amygdala at extinction retention. These findings suggest that DCS improves extinction learning in adolescents because it augments OFC contributions to extinction learning, enabling better medial prefrontal contributions to extinction retention.

T13. D-Cycloserine Facilitates Fear Extinction in Adolescent Rats and Differentially Affects Medial and Lateral Prefrontal Cortex Activation

Adolescents, both humans and rodents, exhibit a marked impairment in extinction of learned fear relative to both younger (i.e., juveniles) and older (i.e., adults) groups. This impairment could be due to the medial or lateral prefrontal cortex (PFC) not being efficiently recruited during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist D-cycloserine (DCS), which enhances exposure therapy in humans with anxiety disorders, overcomes the extinction retention deficit in adolescent rats. The present experiments investigated the effects of DCS on the PFC and amygdala by measuring pMAPK-immunoreactive (IR) neurons.

A Novel Retrieval-Dependent Memory Process Revealed by the Arrest of ERK1/2 Activation in the Basolateral Amygdala.

Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state.

Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum

The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder).

Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction.

Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression. The long-lasting impact might be mediated by an enhancement of memory extinction or an impairment of memory reconsolidation. Here, we directly compared the effects of i.p. injections of cannabidiol (10 mg/kg) with those of the NMDA receptor antagonist MK-801 (0.1 mg/kg) and partial agonist D-cycloserine (DCS; 15 mg/kg) in order to determine the mnemonic basis of long-term fear reduction. We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test. The latter test reduction was replicated by DCS, but MK-801 instead elevated test freezing. In contrast, when initial conditioning was weaker, CBD and MK-801 had similar effects to increase freezing at the fear retention test relative to vehicle controls, whereas DCS had no observable impact. This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.

The NMDA receptor partial agonist d-cycloserine does not enhance motor learning

Rationale:There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning.Methods:Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task.Results:D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses).Conclusion:The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms.

Failure to Recognize Novelty after Extended Methamphetamine Self-Administration Results from Loss of Long-Term Depression in the Perirhinal Cortex.

Exposure to methamphetamine (meth) can produce lasting memory impairments in humans and rodents. We recently demonstrated that extended access meth self-administration results in novel object recognition (NOR) memory deficits in rats. Recognition of novelty depends upon intact perirhinal (pRh) cortex function, which is compromised by meth-induced downregulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors. NMDA receptors containing this subunit have a critical role in pRh long-term depression (LTD), one of the primary physiological processes thought to underlie object recognition memory. We hypothesized that meth-induced downregulation of GluN2B receptors would compromise pRh LTD, leading to loss of NOR memory. We found that meth self-administration resulted in an inability to induce pRh LTD following 1 Hz stimulation, an effect that was reversed with bath application of the NMDA receptor partial agonist D-cycloserine (DCS). In addition, pRh microinfusion of DCS restored meth-induced memory deficits. Furthermore, blockade of GluN2B-containing NMDA receptors with Ro 25-6981 prevented DCS restoration of pRh LTD in meth subjects. Thus, targeting pRh LTD may be a promising strategy to treat meth-induced cognitive impairment.

Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity

The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B-containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism.

The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear

The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.

Double dissociation between the anterior cingulate cortex and nucleus accumbens core in encoding the context versus the content of pavlovian cocaine cue extinction.

One strategy proposed to treat addictive disorders is to extinguish the association between environmental stimuli (cues) and actions associated with drug use to reduce relapse. The context specificity of extinction learning, however, impairs the ability of addicts to generalize extinction training to the drug-taking context. We previously reported that the NMDA receptor partial agonist d-cycloserine administered after pavlovian extinction of cocaine cues in the nucleus accumbens core (NAc) reduced cue-induced renewal. Nevertheless, it was unclear whether this was due to disrupted contextual encoding of extinction or enhanced extinction consolidation. Thus, we examined the effect of the NMDA receptor antagonist d-AP5 on context encoding versus cue extinction learning. We also determined the role of the anterior cingulate cortex (ACC) in encoding the cue extinction memory or the context, due to its projections to NAc, and hypothesized the role in conflict monitoring and contextual modulation of decision making. Using rats, we observed that NMDA receptor antagonism in the NAc did not alter context encoding but did interfere with acquisition of the cue extinction memory, i.e., learning, conversely inactivation of the ACC reduced the contextual encoding of extinction but did not interfere with the acquisition or expression of extinction. The observed effects were not present in the absence of cue extinction training. Additionally, the contextual memory did not appear to be consolidated in the ACC as neither postsession inactivation nor protein synthesis inhibition impaired context-appropriate responding. These results have implications for overcoming the context specificity of extinction to treat psychiatric disorders including addiction.

Learning deficits in an odor reward-task induced by parafascicular thalamic lesions are ameliorated by pretraining d-cycloserine in the prelimbic cortex

We investigated whether the N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) infused into the prelimbic cortex (PLC) would reverse the learning deficits caused by bilateral excitotoxic lesions of the parafascicular nucleus (PFn) in an odor discrimination task (ODT). Rats with PFn lesions received a bilateral infusion of DCS (10μg/side) into the PLC 20min before ODT acquisition. The task retention was evaluated in a drug-free test carried out 24h later. DCS significantly attenuated the PFn lesion-induced deficits as measured by both latency to nose-poke the rewarded odor and number of errors committed during ODT acquisition and retention. Therefore, DCS may be an enhancing memory treatment in animal models of cognitive impairment, such as PFn-lesioned rats. The PFn contribution to learning and memory may possibly be linked to its role in the modulation of glutamatergic PLC activity.

D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues

The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

Behavioural memory reconsolidation of food and fear memories

The reactivation of a memory through retrieval can render it subject to disruption or modification through the process of memory reconsolidation. In both humans and rodents, briefly reactivating a fear memory results in effective erasure by subsequent extinction training. Here we show that a similar strategy is equally effective in the disruption of appetitive pavlovian cue–food memories. However, systemic administration of the NMDA receptor partial agonist D-cycloserine under the same behavioural conditions did not potentiate appetitive memory extinction, suggesting that reactivation does not enhance subsequent extinction learning. To confirm that reactivation followed by extinction reflects a behavioural analog of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the LVGCC blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories.

D-Cycloserine for Treatment Nonresponders With Obsessive-Compulsive Disorder: A Case Report

Despite being the most effective treatment available, as many as one third of patients who receive exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) do not initially respond to treatment. Recent research suggests that the n-methyl d-aspartate (NMDA) receptor partial agonist D-Cycloserine (DCS) may speed up the course of ERP for OCD rather than enhance it. Thus, it is unclear whether DCS would benefit patients who have proven nonresponsive to ERP and serotonin reuptake inhibitors. The present study evaluated the ability of DCS to enhance ERP for 2 patients with OCD who previously had failed to show adequate response to treatment using time-series analysis. Both patients experienced greater reductions with DCS augmented ERP than they did with prior treatment; however, 1 patient relapsed by the 1-month follow-up. DCS augmented ERP might be an effective method for boosting outcomes in individuals who do not readily respond to ERP.

D-Cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window

It has been long thought that hyperactivation of N-methyl- d-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4 h to 2 weeks after brain injury, activation at 24 h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist d-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p.) DCS or vehicle once (8, 16, 24, or 72 h) twice (24 and 48 h) or three times (24, 48 and 72 h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72 h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8 h or 16 h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24 h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h or by cresyl violet at 28 days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24 h.

D-Cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversion

We investigated whether the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS, 20 microg/side) microinfused into the basolateral amygdala (BLA) would reverse stress-induced impairment of extinction in two aversive learning paradigms: contextual fear conditioning and conditioned taste aversion (CTA). We found that DCS in the BLA show differential involvement in the extinction of these two paradigms and in its modulation of stress-induced impairment of extinction. This may suggest that the dysfunctional extinction of fear and taste aversion following exposure to a stressful experience may be modulated by different mechanisms.

D-Cycloserine Facilitates Extinction of Naloxone-Induced Conditioned Place Aversion in Morphine-Dependent Rats

Cues paired with drug administration trigger relapse to drug seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus in the absence of the unconditioned stimulus with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently, they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS) was administered before extinction training. Morphine withdrawal-induced CPA persists in the absence of extinction training. Administration of DCS before extinction training facilitates extinction. D-cycloserine facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction.

Targeting the NMDA Receptor for Fear-Related Disorders

The gap between basic neuroscience and clinical psychiatry in the treatment of anxiety disorders has been steadily diminishing over recent years. Among the leading advances in this field of translation research is the application of knowledge on the neurobiology of fear memory to the treatment of anxiety disorders in humans. Animal studies have identified N-methyl-D-aspartate (NMDA) receptors as crucial in fear memory acquisition and consolidation, as well as in its extinction and reconsolidation. Based on this, the NMDA receptor partial agonist D-cycloserine, which facilitates fear extinction in rodents, has been shown to increase the effect of exposure therapy in psychiatric patients for conditions such as phobias, social anxiety and obsessive-compulsive disorder. In this article, we review current strategies for targeting the NMDA receptor in the treatment of fear-related disorders, analyzing experimental results, clinical data, and recent patents in the field, while also addressing potential new approaches to explore this field of drug discovery.

D-Cycloserine enhances memory consolidation of hippocampus-dependent latent extinction

Adult male Long-Evans rats were trained to run in a straight-alley maze for food reward and subsequently received hippocampus-dependent latent extinction training. Immediately following latent extinction, rats received peripheral injections of the NMDA receptor partial agonist D-cycloserine (DCS, 15 mg/kg), or saline. Twenty-four hours later, rats received four extinction "probe" trials. Relative to saline controls, latencies to reach the goal box on probe trials were significantly higher in rats that had received DCS. These findings indicate that memory consolidation underlying hippocampus-dependent latent extinction, a cognitive form of learning in which the previously rewarded response is not made during extinction training, can be enhanced by NMDA-receptor agonism.