NMDA Glutamate Receptor Antagonist Research Articles

Effect of oral caroverine in the treatment of tinnitus: A quasi-experimental study

ABSTRACT Objective: Caroverine is an antagonist of non-NMDA and NMDA glutamate receptors. Cochlear synaptic tinnitus arises from a synaptic disturbance of NMDA or non-NMDA receptors on the afferent dendrites of spiral ganglion neurons. This forms a basis for the use of caroverine in the treatment of tinnitus. Hence, the present study was carried out to find the effect of oral caroverine in the treatment of tinnitus. Methodology: This quasi-experimental study was carried out on sixty consecutive patients of tinnitus. Thirty patients were given the usual standard of care consisting of Tab. Cinnarizine 25mg twice daily along with fixed dose combination Cap. B-complex and Ginkgo biloba once daily for ninety days and thirty patients were given Cap. Caroverine 40mg, twice daily for ninety days. Outcome assessment was done using the tinnitus case history questionnaire, tinnitus handicap inventory score, and VAS. The data were analyzed using GraphPad Prism Trial Version. A P value ≤ 0.05 was taken as statistically significant. Results: There was a significant improvement in the tinnitus case history questionnaire score at 90 days in patients suffering from mild tinnitus when treated with caroverine. There was a larger decrease in the tinnitus handicap inventory score at 90 days of treatment in the caroverine-treated patients. The median VAS showed an improvement in the caroverine-treated group. The overall reduction in tinnitus in the caroverine-treated group was 53.3% with an odds ratio, 95% CI of 0.375 (0.12-1.08). Conclusion: Oral caroverine was found to be better than the usual standard of care in reducing mild cochlear synaptic tinnitus. It also improved sensory–neural hearing loss during the treatment period.

Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR.

Administration of low dose intranasal ketamine exerts a neuroprotective effect on whole brain irradiation injury model in wistar rats.

Exposure to ionizing radiation leads to oxidative stress and neuroinflammation, resulting in neurocognitive impairments. Adverse effects are also associated with glutamate-induced excitotoxicity due to alterations in the composition of glutamate receptors. Ketamine, which is a noncompetitive NMDA glutamate receptor antagonist, has been stated to exert an impact on glutamatergic receptors. This study aims to reveal the possible alleviating or preventive effects of ketamine, which maintains glutamate homeostasis and decreases neurodegeneration, in a radiation-induced neurotoxicity model. Twenty-one female Wistar Queryrats were included in the study and 14 of these underwent whole brain irradiation (IR) with a 20 Gray single dose. Animals were allocated into three groups. Group 1: Normal control; Group 2: Placebo / IR + Saline; Group 3: IR + Ketamine. Ketamine was administered in addition to IR to rats in Group 3. The one-way ANOVA statistical test was used to compare groups. The value of p < 0.05 was considered statistically significant. When administered in addition to irradiation, ketamine treatment significantly increased scores in the three-chamber sociability test, open field test, and passive avoidance learning test. It also raised neuron counts in the hippocampal CA1 and CA3 regions as well as in Purkinje cells, and enhanced levels of brain-derived neurotrophic factor and tyrosine receptor kinase-B. Furthermore, ketamine administration resulted in decreased levels of glial fibrillary acidic protein, malondialdehyde, and tumor necrosis factor-alpha, indicating a reduction in neuroinflammation and oxidative stress. Ketamine exerted a significant protective impact on radiation-induced neurocognitive impairments and enhanced social-memory capacity by reducing neuronal loss, oxidative stress, and neuroinflammation. Our findings suggest that ketamine is beneficial in the treatment or prevention of neurodegeneration via the regulation of the BDNF/TrkB signaling pathway besides decreasing neuroinflammation and blocking NMDA receptors.

Effects of systemic pretreatment with the NAALADase inhibitor 2-PMPA on oral methamphetamine reinforcement in C57BL/6J mice.

Repeated exposure to methamphetamine (MA) in laboratory rodents induces a sensitization of glutamate release within the corticoaccumbens pathway that drives both the rewarding and reinforcing properties of this highly addictive drug. Such findings argue the potential for pharmaceutical agents inhibiting glutamate release or its postsynaptic actions at glutamate receptors as treatment strategies for MA use disorder. One compound that may accomplish both of these pharmacological actions is the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA). 2-PMPA elevates brain levels of the endogenous agonist of glutamate mGluR3 autoreceptors, N-acetyl-aspartatylglutamate (NAAG), while potentially acting as an NMDA glutamate receptor antagonist. Of relevance to treating psychomotor stimulant use disorders, 2-PMPA is reported to reduce indices of both cocaine and synthetic cathinone reward, as well as cocaine reinforcement in preclinical rodent studies. Herein, we conducted three experiments to pilot the effects of systemic pretreatment with 2-PMPA (0-100 mg/kg, IP) on oral MA self-administration in C57BL/6J mice. The first experiment employed female mice with a prolonged history of MA exposure, while the mice in the second (females) and third (males and females) experiment were MA-naïve prior to study. In all experiments, mice were trained daily to nose-poke for delivery of unadulterated MA solutions until responding stabilized. Then, mice were pretreated with 2-PMPA prior to operant-conditioning sessions in which nose-poking behavior was reinforced by delivery of 120 mg/L or 200 mg/L MA (respectively, in Experiments 1 and 2/3). Contrary to our expectations, 30 mg/kg 2-PMPA pretreatment altered neither appetitive nor consummatory measures related to MA self-administration. In Experiment 3, 100 mg/kg 2-PMPA reduced responding in the MA-reinforced hole, as well as the number of reinforcers earned, but did not significantly lower drug intake. These results provide mixed evidenced related to the efficacy of this NAALADase inhibitor for reducing oral MA reinforcement in female mice.

Effect of intermittent subchronic MK-801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex.

The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist. In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system. Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment. These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.

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.

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.

Financement de la psychiatrie en France, la question des médicaments onéreux : exemple de l’Esketamine dans l’épisode dépressif caractérisé résistant

In France, the funding of mental health institutions relies on an annual budget allocation. Esketamine, a non-competitive NMDA glutamate receptor antagonist, has been approved for adults with treatment-resistant major depressive disorder since 2019. However, due to its high cost (€200 per 28 mg device, excluding tax), the aim of this work was to evaluate whether the income received by an institution for the management of a patient treated with Esketamine could cover the purchase of devices, based on real clinical data. Within our institution, seven patients underwent treatment with Esketamine during the study period resulting in a total usage of 714 devices, amounting to a purchase cost of €142,800. Over the course of the follow-up period, the institution received €149,054 in revenue for the treatment of these patients. Our analysis reveals that the expense associated with Esketamine constitutes 95.8 % of the income generated from caring for these patients. This not only raises questions about the pricing of this drug but also highlights the lack of a funding system for costly psychiatric drugs. This concern extends to somatic treatments associated with psychiatric care.

Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors.

The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear.

Epigenetic Processes of DNA Methylation Are Selectively Involved in the Mechanisms of Retrograde and Anteograde Amnesia.

The participation of DNA methylation processes in the mechanisms of anterograde and retrograde amnesia caused by impaired reconsolidation of conditioned food aversion memory by NMDA glutamate receptor antagonists or serotonin receptor antagonists, respectively, were studied on grape snails. Anterograde amnesia was characterized by impaired formation of long-term memory during repeated learning. Administration of a DNA methyltransferase (DNMT) inhibitor to amnestic animals resulted in accelerated formation of long-term memory during 1 day of repetitive training vs 3 days during initial training. In serotonin-dependent retrograde amnesia, repeated learning without DNMT inhibitor administration or after inhibitor injections led to the formation of long-term memory. The dynamics of memory formation was similar in both cases and did not differ from that during the initial training: the memory was formed within 3 days of training. Thus, epigenetic processes of DNA methylation are selectively involved in the mechanisms of anterograde amnesia, but do not participate in the mechanisms of retrograde amnesia.

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.

Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats.

Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact. We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs. No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline. This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.

Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review.

Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive-aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive-aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility.

Comparative Study of the Effect of a DNA Methyltransferase Inhibitor and a Histone Deacetylase Inhibitor on Memory Formation Processes in Anterograde Amnesia.

The participation of DNA methylation and histone acetylation in the mechanisms of anterograde amnesia and memory recovery was studied on grape snails trained in conditioned food aversion. Anterograde amnesia developed 10 days after memory reconsolidation impairment with an NMDA glutamate receptor antagonist and was characterized by long-term memory formation impairment upon repeated training. DNA methyltransferase inhibitor injections to snails 1 h before repeated training, as well as 15 min or 4 h after repeated training, caused rapid formation of memory that persisted for at least 10 days. Injections of histone deacetylase inhibitor before repeated training also induced the formation of a stable long-term memory. However, administration of histone deacetylase inhibitor 15 min after repeated training initiated a temporary memory recovery. Injections of the inhibitor 4 h after repeated training were ineffective. These results indicate that histone-dependent chromatin remodeling and DNA methylation are selectively involved in the mechanisms of anterograde amnesia and memory recovery.

O010 / #862 FRONTOPARIETAL TDCS DECREASES PSYCHOSIS-RELEVANT OSCILLOPATHIES: A PRECLINICAL PROOF OF THERAPEUTIC CONCEPT: TRACK 2: BRAIN STIMULATION

During the prodromal phase of schizophrenia with its complex and insidious clinical picture, EEG recordings detect widespread oscillation disturbances (or oscillopathies) during the wake-sleep cycle. Neural oscillations are electro-biomarkers of the connectivity state within systems. A single systemic psychotomimetic administration of ketamine, a non-competitive NMDA glutamate receptor antagonist, transiently reproduces the oscillopathies with a clinical picture reminiscent of the psychosis prodrome.

DNA methylation inhibition participates in the anterograde amnesia key mechanism through the suppression of the transcription of genes involved in memory formation in grape snails

The study of the amnesia mechanisms is of both theoretical and practical importance. The mechanisms of anterograde amnesia are the least studied, due to the lack of an experimental model that allows studying this amnesia type molecular and cellular mechanisms. Previously, we found that conditional food aversion memory reconsolidation impairment in snails by NMDA glutamate receptor antagonists led to the amnesia induction, in the late stages of which (>10 days) repeated training did not cause long-term memory formation. In the same animals, long-term memory aversion to a new food type was formed. We characterized this amnesia as specific anterograde amnesia. In the present work we studied the role of epigenetic DNA methylation processes as well as protein and mRNA synthesis in the mechanisms of anterograde amnesia and memory recovery. DNMT methyltransferase inhibitors (iDNMT: zebularine, RG108 (N-Phthalyl-1-tryptophan), and 5-AZA (5-Aza-2'-deoxycytidine)) were used to alter DNA methylation. It was found that in amnesic animals the iDNMT administration before or after shortened repeated training led to the rapid long-term conditional food aversion formation (Ebbinghaus saving effect). This result suggests that amnestic animals retain a latent memory, which is the basis for accelerated memory formation during repeated training. Protein synthesis inhibitors administration (cycloheximide) before or immediately after repeated training or administration of RNA synthesis inhibitor (actinomycin D) after repeated training prevented memory formation under iDNMT action. The earlier protein synthesis inhibitor effect suggests that the proteins required for memory formation are translated from the pre-existing, translationally repressed mRNAs. Thus, we have shown for the first time that the anterograde amnesia key mechanism is DNMT-dependent suppression of the transcription of genes involved in memory mechanisms. Inhibition of DNMT during repeated training reversed these genes expression blockade, opening access to them by transcription factors synthesized during training from the pre-existing mRNAs.

NMDA receptors in the insular cortex modulate cardiovascular and autonomic but not neuroendocrine responses to restraint stress in rats

The insular cortex (IC) is a brain structure involved in physiological and behavioural responses during stressful events. However, the local neurochemical mechanisms involved in control of stress responses by the IC are poorly understood. Thus, this study aimed to investigate the involvement of glutamatergic neurotransmission within the IC in cardiovascular, autonomic and neuroendocrine responses to an acute session of restraint stress. For this, the selective NMDA glutamate receptor antagonist LY235959 (1 nmol/100 nL) or the selective non-NMDA glutamate receptor antagonist NBQX (1 nmol/100 nL) were microinjected into the IC 10 min before the onset of the 60 min session of restraint stress. We observed that the antagonism of NMDA receptors within the IC enhanced the restraint-evoked increase in arterial pressure and heart rate, while blockade of non-NMDA receptors did not affect these cardiovascular responses. Spontaneous baroreflex analysis demonstrated that microinjection of LY235959 into the IC decreased baroreflex activity during restraint stress. The decrease in tail skin temperature during restraint stress was shifted to an increase in animals treated with the NMDA receptor antagonist. Nevertheless, the blockade of either NMDA or non-NMDA glutamate receptors within the IC did not affect the increase in circulating corticosterone levels during restraint stress. Overall, our findings provide evidence that IC glutamatergic neurotransmission, acting via local NMDA receptors, plays a prominent role in the control of autonomic and cardiovascular responses to restraint stress, but without affecting neuroendocrine adjustments.

Glutamate NMDA Receptor Antagonists with Relevance to Schizophrenia: A Review of Zebrafish Behavioral Studies.

Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Frequently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomotor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further characterize the major differences in behavior as compared to mammals.

The Role of DNA Methylation and Activity of Neurotransmitter Receptors in the Mechanisms of Specific Anterograde Amnesia and Memory Recovery.

Impairment of reconsolidation of conditioned food aversion memory led to the development of a specific anterograde amnesia: repeated training of amnestic snails did not induce long-term memory formation. DNA demethylation caused by injections of DNA methyltransferase inhibitor (DNAMT) during repeated training led to long-term memory formation. Injections of an NMDA glutamate receptor antagonist or a serotonin receptor antagonist prevented memory formation induced by administration of DNAMT inhibitor and repeated training. We hypothesize that methylation-dependent repression of neuronal genes underlies anterograde amnesia. Demethylation eliminated the blockade of these genes and created conditions for long-term memory formation, the induction mechanisms of which involve neurotransmitter receptors.

N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats.

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.