NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus.

NMDA receptors (NMDARs) modulate glutamatergic excitatory tone in the brain via two complementary modalities: a phasic excitatory postsynaptic current and a tonic extrasynaptic modality. Here, we demonstrated that the tonic NMDAR-current (I NMDA) mediated by NR2A-containing NMDARs is an efficient biosensor detecting the altered ambient glutamate level in the supraoptic nucleus (SON). I NMDA of magnocellular neurosecretory cells (MNCs) measured by nonselective NMDARs antagonist, AP5, at holding potential (V holding) -70 mV in low concentration of ECF Mg2+ ([Mg2+]o) was transiently but significantly increased 1-week post induction of a DOCA salt hypertensive model rat which was compatible with that induced by a NR2A-selective antagonist, PEAQX (I PEAQX) in both DOCA-H2O and DOCA-salt groups. In agreement, NR2B antagonist, ifenprodil, or NR2C/D antagonist, PPDA, did not affect the holding current (I holding) at V holding -70 mV. Increased ambient glutamate by exogenous glutamate (10 mM) or excitatory amino acid transporters (EAATs) antagonist (TBOA, 50 mM) abolished the I PEAQX difference between two groups, suggesting that attenuated EAATs activity increased ambient glutamate concentration, leading to the larger I PEAQX in DOCA-salt rats. In contrast, only ifenprodil but not PEAQX and PPDA uncovered I NMDA at V holding +40 mV under 1.2 mM [Mg2+]o condition. I ifenprodil was not different in DOCA-H2O and DOCA-salt groups. Finally, NR2A, NR2B, and NR2D protein expression were not different in the SON of the two groups. Taken together, NR2A-containing NMDARs efficiently detected the increased ambient glutamate concentration in the SON of DOCA-salt hypertensive rats due to attenuated EAATs activity.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.

Long-term efficacy and safety of perampanel as an add-on therapy in patients with epilepsy.

BACKGROUND: Perampanel (PER) is a newly developed amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist that has been globally approved for the treatment of both focal and generalized seizures. The efficacy and safety of PER have only been reported over short periods of treatment so far. This study aims to clarify the long-term efficacy and safety of PER as an add-on therapy. METHOD: This retrospective observational study investigated 176 epilepsy patients who received PER as add-on medical therapy in two Japanese epilepsy centers between June 2016 and July 2022. The adherence, seizure frequency, and plasma concentration of PER were evaluated at three time points: 6 months, 12 months, and 24 months or longer after the start of adjunctive PER treatment. RESULTS: 112 patients undergoing PER treatment were evaluated at 6 months, 86 were evaluated at 12 months, and 52 were evaluated at 24 months or longer. Overall, 42.9 % (48/112), 45.4 % (40/86), and 44.2 % (23/52) of the patients were seizure-free at 6, 12, and 24 months or longer, respectively. The rate of PER tolerance was 78.3 %, 69.9 %, and 54.7 % at 6, 12, and 24 months or longer, respectively. At the latest timepoint, the seizure-free group was taking a significantly lower dose of PER than the seizure-remnant group, and the number of anti-seizure medications (ASMs) was associated with seizure outcomes. In addition, the seizure-free rate was significantly higher in patients who received PER as a first add-on than in those who received it as a late add-on. No significant difference was found in the plasma concentration of PER between the seizure-free and seizure-remnant groups at 24 months or longer. Among the patients receiving PER at dose of 2 mg, however, the plasma concentrations were significantly higher in the seizure-free group than in the seizure-remnant group (282.7 ± 109.8 µg/ml vs 94.7 ± 54.9 µg/ml, p = 0.0024). CONCLUSION: This long-term retrospective observational study provides evidence of the efficacy and safety of PER over 2 years treatment period in Japan. Notably, patients who started on PER as the first add-on showed a better seizure outcome than those who received it as a late add-on over the long term. Measured plasma concentrations may provide valuable guidance for the management of patients. Higher plasma concentration at low dose PER may suggest the better seizure control.

Acute and chronic glutamate NMDA antagonist treatment attenuates dopamine D1 antagonist-induced reduction of nicotine self-administration in female rats.

Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.

The role of glutamate NMDA receptors of the mediodorsal thalamus in scopolamine-induced amnesia in rats.

The current study was designed to examine the role of glutamate NMDA receptors of the mediodorsal thalamus (MD) in scopolamine-induced memory impairment. Adult male rats were bilaterally cannulated into the MD. According to the results, intraperitoneal (i.p.) administration of scopolamine (1.5 mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the glutamate NMDA receptors agonist, N-Methyl-D-aspartic acid (NMDA; 0.05 µg/rat), into the MD significantly improved scopolamine-induced memory consolidation impairment. Co-administration of D-AP5, a glutamate NMDA receptor antagonist (0.001-0.005 µg/rat, intra-MD) potentiated the response of an ineffective dose of scopolamine (0.5 mg/kg, i.p.) to impair memory consolidation, mimicking the response of a higher dose of scopolamine. Noteworthy, post-training intra-MD microinjections of the same doses of NMDA or D-AP5 alone had no effect on memory consolidation. Moreover, the blockade of the glutamate NMDA receptors by 0.003 ng/rat of D-AP5 prevented the improving effect of NMDA on scopolamine-induced amnesia. Thus, it can be concluded that the MD glutamatergic system may be involved in scopolamine-induced memory impairment via the NMDA receptor signaling pathway.

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.

A Network Model of the Modulation of γ Oscillations by NMDA Receptors in Cerebral Cortex.

Psychotic drugs such as ketamine induce symptoms close to schizophrenia and stimulate the production of γ oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating γ oscillations, and have integrated the action of drugs such as ketamine to partially block NMDA receptors (NMDARs). The model can reproduce the paradoxical increase of γ oscillations by NMDA receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channels are blocked, an increase of γ power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to γ states, but also to asynchronous states with no apparent γ. We conclude that NMDA antagonists induce an increased excitability state, which may or may not produce γ oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

The protective effect of N-acetylcysteine against MK-801-induced neurodegeneration in mice.

BACKGROUND: Neurological disorders result in not only a decline in the quality of life of patients but also a global economic burden. Therefore, protective medicine becomes more important for society. MK-801 is a chemical agent used to understand the etiology of behavioral disorders and brain degeneration in animal models. This study aims to determine whether N-acetylcysteine (NAC) is useful to treat brain degeneration caused by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. METHODS AND RESULTS: Four groups were formed by dividing 24 male BALB/c mice into groups of six. The control group was given a saline solution (10 ml/kg-i.p.). MK-801 (1 mg/kg-i.p.) was given alone to one group, and it was given with NAC (100 mg/kg-i.p.) to another group, while the last group was given only NAC (100 mg/kg-i.p.). The administration of drugs lasted for fourteen days. After the behavioral tests (open field and elevated plus-maze), all animals were euthanised, and brain tissues were collected for real-time PCR, TAS-TOS analysis, hematoxylin-eosin, Kluver-Barrera, and TUNEL staining. In the MK-801 group, besides nuclear shrinkage in neurons, glial cell infiltration, vacuolization in cortical neurons, white matter damage, and apoptosis were observed. CONCLUSION: In the mice given NAC as a protective agent, it was observed that behavioral problems improved, antioxidant levels increased, and nuclear shrinkage, glial cell infiltration, vacuolization in neurons, and white matter degeneration were prevented. Moreover, MBP expression increased, and the number of TUNEL-positive cells significantly decreased. As a result, it was observed that NAC may have a protective effect against brain degeneration.

The Role of NMDA Receptor Subunits in the Effect of Memantine on the Brain of Healthy Animals.

The non-competitive NMDA glutamate receptor antagonist memantine has neuroprotective properties and is the first non-cholinergic drug approved for the treatment of Alzheimer's disease. The purpose of this work was to test the hypothesis that injections of memantine to healthy animals can affect the subunit composition of NMDA receptors in the brain, which may explain the effects of its chronic administration. For this, the expression of subunits GluN1, GluN2A, GluN2B, and GluN2C was studied in the hippocampus and prefrontal cortex of rats after single or five subchronic injections of memantine. The results showed that the GluN2C subunit (GRIN2C) plays an important role in the effects of memantine; against the background of memantine treatment, the expression of this subunit markedly decreased in the prefrontal cortex, but not in the hippocampus, which significantly affected the excitation/inhibition balance in cortical structures.

Role of kainate receptors in pruriceptive processing in the mouse spinal cord.

Pruritus, including neuropathic and psychogenic pruritus, is an unpleasant feeling that causes a desire to scratch, which negatively impacts physical and psychological aspects of daily life. Nonetheless, little is known about the neural mechanisms involved in pruritus. Glutamate is a predominant excitatory neurotransmitter in the mammalian central nervous system and exerts its effects by binding to various glutamate receptors, including kainate (KA) receptors; however, the precise involvement of each glutamate receptor in pruriceptive processing remains unclear, particularly that of KA receptors. Therefore, the roles of KA receptors in histamine-dependent and -independent itch were investigated using CNQX, an AMPA/KA receptors antagonist, UBP310 and UBP302, antagonists of KA receptors, and small interfering (si)RNAs against KA receptor subunits in mice with acute and chronic pruritus. The effects of KA receptor antagonists on histamine-induced c-Fos expression in the spinal cord were also examined. The intrathecal administration of CNQX reduced the number of scratching events induced by histamine and chloroquine. On the other hand, UBP310 or UBP302 and the siRNAs of KA receptor subunits 1-3 significantly inhibited the induction of scratching events in mice treated with histamine, while no significant change was observed in the induction of spontaneous scratching events in mice with chronic pruritus. In addition, antagonists of KA receptors attenuated c-Fos expression in the superficial layers of the dorsal horn induced by histamine. These results indicate that KA receptors are involved in acute pruriceptive processing in the spinal cord induced by histamine, but not chloroquine or chronic itch.

One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25-6981, increases glutamate neurotransmission and induces antidepressant-like effects.

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N-methyl-D-aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult-born GCs for antidepressant-like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B-containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)-(4-hydroxyphenyl)-(ßS)-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 µg each side) following a chronic fluoxetine (18 mg/kg/day) treatment-known to increase adult hippocampal neurogenesis-in a mouse model of anxiety/depression. Responses in a neurogenesis-dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma-aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid-acting antidepressant-like effect of local Ro25-6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine-independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.

Nasal administration of orexin A partially rescues dizocilpine-induced cognitive impairments in female C57BL/6 J mice.

Sex difference has been reported in several behavioral endophenotypes of neuropsychiatric disorder in both rodents and humans. However, sex difference in cognitive symptoms associated with neuropsychiatric disorders has not been studied in detail. In this study, we induced cognitive impairment using the NMDA receptor antagonist, dizocilpine (MK-801), in male and female C57BL/6 J mice and performed a visual discrimination task in an automated touchscreen system. We found that discrimination performance decreased with increased doses of MK-801 in both sexes. However, female mice showed stronger deficit in discrimination performance than the male mice especially after administration of low (0.01 mg/kg) and high (0.15 mg/kg) doses of MK-801. Furthermore, we tested if administration of orexin A, orexin-1 receptor antagonist SB-334867 or orexin-2 receptor antagonist EMPA rescued MK-801 (0.15 mg/kg) induced cognitive impairment in visual discrimination. We found that nasal administration of orexin A partially rescued the cognitive impairment induced by MK-801 in females but not in males. Taken together, our data show that female C57BL/6 J mice are more sensitive compared to males to some doses of MK-801 in discrimination learning task and that orexin A partially rescues this cognitive impairment in females.

The Effect of Ketamine on Endoplasmic Reticulum Stress in Rats with Neuropathic Pain.

This study aimed to investigate the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on endoplasmic reticulum (ER) stress in rats with neuropathic pain (NP). NP was induced in rats through ligation and transection of the sciatic nerve. After confirmation of NP, the animals were randomly divided into ketamine and control groups. The ketamine group was administered 50 mg/kg of ketamine at 15, 18, and 21 days after surgery. The expression of NMDA receptor subtype 2B (NR2B) and ER stress markers in the spinal cord (L5) was evaluated. The ipsilateral side of the surgery in the ketamine group was less sensitive to mechanical and cold stimulations. The expression of NR2B on the ipsilateral side was significantly lower in the ketamine group than in the control group (18.93 ± 1.40% vs. 31.08 ± 0.74%, p < 0.05). All markers for ER stress on the ipsilateral side of the surgery in both groups had higher expression than those on the contralateral side. The expression of activating transcription factor-6 (ATF-6) on the ipsilateral side was significantly lower in the ketamine group than in the control group (p < 0.05). Systemic administration of ketamine inhibited the expression of NMDA receptors and improved NP symptoms. Among the markers of ER stress, the therapeutic effect of ketamine is associated with the inhibition of ATF-6 expression.

The NMDA receptor antagonists memantine and ketamine as anti-migraine agents.

Migraine is a debilitating disorder affecting females more frequently than males. There is some evidence that drugs targeting glutamate receptors: memantine and ketamine might be beneficial in the therapy of this entity. Therefore, the purpose of this work is to present NMDA receptor antagonists, memantine and ketamine, as potential anti-migraine agents. We searched PubMed/MEDLINE, Embase, and clinical trials submitted to ClinicalTrials.gov to find publications describing eligible trials published between database inception and December 31, 2021. This comprehensive literature review summarizes data on the use of the NMDA receptor antagonists memantine and ketamine in the pharmacotherapy of migraine. Results from 20 previous and recent preclinical experiments are discussed and correlated with 19 clinical trials (including case series, open-label, and randomized placebo-controlled trials). For the purposes of this review, the authors hypothesized that the propagation of SD is a major mechanism in the pathophysiology of migraine. In several animal studies and in vitro studies, memantine and ketamine inhibited or reduced propagation of the SD. In addition, the results of clinical trials suggest that memantine or ketamine may be an effective treatment option for migraine. However, most studies on these agents lack control group. Although further clinical trials are needed, the results suggest that ketamine or memantine may be promising molecules for the treatment of severe migraine. Particular attention should be paid to people who have a treatment-resistant form of migraine with aura or have exhausted existing treatment options. For them, the drugs under discussion could represent an interesting alternative in the future.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain.

INTRODUCTION: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. METHODS: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). RESULTS: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. CONCLUSION: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.