scholarly journals Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1026
Author(s):  
Kristina Holubova ◽  
Marketa Chvojkova ◽  
Barbora Hrcka Krausova ◽  
Vojtech Vyklicky ◽  
Eva Kudova ◽  
...  
Keyword(s):  
Animal Model ◽  
Nmda Receptor ◽  
Neuroactive Steroids ◽  
Stress Exposure ◽  
Mk 801 ◽  
Receptor Modulator ◽  
Receptor Modulation ◽  
Antipsychotic Effect ◽  
Response To Stress ◽  
Systemic Application

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

scholarly journals Effect of dizocilpine (MK-801) on the working memory of rats on a three-panel runway apparatus

2018 ◽  
Vol 7 (12) ◽  
pp. 2373
Author(s):  
Naveen Kumar ◽  
Navin Budania ◽  
Arka Mondal ◽  
Sana Tafseer ◽  
Siddarth Ahuja ◽  
...  
Keyword(s):  
Working Memory ◽  
Animal Model ◽  
Nmda Receptor ◽  
Animal Models ◽  
Receptor Antagonist ◽  
Cognitive Deficits ◽  
Latency Period ◽  
Nmda Receptor Antagonist ◽  
Memory Errors ◽  
Mk 801

Background: Understanding the processes underlying cognitive functions is a prerequisite to develop strategies for the treatment of cognitive deficits. There is a great need for valid animal models for investigating the cognitive enhancing effects of potential therapeutics. Many studies have investigated animal models of cognitive deficits by using animals treated with compounds that compromise cognitive abilities. Glutamate, an excitatory neurotransmitter and abundantly distributed in the central nervous system is involved in memory processes through N-methyl-d-aspartate (NMDA) receptors. The behavioural consequences of blocking the NMDA receptor provide the rationale for cognitive impairment as an animal model for the cognitive deficits associated with dementia. Authors investigated the effect of dizocilpine (MK-801), an NMDA-receptor antagonist (non-competitive) on the working memory in rats using the three-panel runway apparatus.Methods: Total 24 trained male albino rats were randomly divided into 4 groups of 6 animals each. Varying doses of MK-801 were administered to the animals. Working memory errors and latency periods were evaluated on the three panel Runway apparatus.Results: Treatment with MK-801 at the dose of 0.03mg/ kg did not result in any significant change in working memory errors or latency period in comparison to saline control. MK-801 treatment at dose of 0.1mg/kg and 0.3mg/kg resulted in a significant increase in the number of working memory errors and latency period as compared to control.Conclusions: Authors conclude that MK-801 treatment in the dose of 0.1mg/ kg and 0.3mg/kg resulted in working memory deficits on the three-panel runway apparatus. Rats with cognitive deficits induced by the prototypical N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 may provide a relevant animal model of dementia based on the mechanistic approach of blocking NMDA/glutamatergic signalling.

scholarly journals In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yo-Han Joo ◽  
Yun-Kwan Kim ◽  
In-Gyu Choi ◽  
Hyeon-Jin Kim ◽  
Young-Don Son ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Glucose Metabolism ◽  
Cerebral Glucose Metabolism ◽  
Functional Coupling ◽  
Resonance Spectroscopy ◽  
Acute Administration ◽  
Multimodal Neuroimaging ◽  
Mk 801 ◽  
Genetic Ablation ◽  
Neuroimaging Study

Abstract Background Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. Methods We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. Results Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). Conclusions This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

scholarly journals Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability

2021 ◽  
Vol 22 (15) ◽  
pp. 8091
Author(s):  
Grace Jang ◽  
M. Bruce MacIver
Keyword(s):  
Nmda Receptor ◽  
Potassium Channel ◽  
Receptor Antagonist ◽  
Hippocampal Slices ◽  
Nmda Receptor Antagonist ◽  
Channel Block ◽  
Mk 801 ◽  
Ca1 Region ◽  
Excitatory Transmission ◽  
Ketamine Anesthesia

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.

Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat

1992 ◽  
Vol 76 (1) ◽  
pp. 127-133 ◽  
Author(s):  
Michael C. Wallace ◽  
Graham M. Teasdale ◽  
James McCulloch
Keyword(s):  
Nmda Receptor ◽  
Caudate Nucleus ◽  
Intravenous Administration ◽  
Nmda Receptor Antagonists ◽  
Contralateral Hemisphere ◽  
Receptor Antagonists ◽  
Isotopic Tracer ◽  
Mk 801 ◽  
Ischemic Tissue

✓ The clinical utility of N-methyl-D-aspartate (NMDA) receptor antagonists is now being assessed in ischemic brain injury in humans. The uptake and retention of NMDA receptor antagonists in ischemic tissue will influence the design of clinical trials. The effects of permanent occlusion of the middle cerebral artery, induced 15 minutes prior to isotope administration, on the uptake of 3H-MK-801 (dizocilpine) have been assessed in the rat with quantitative autoradiography. In a group of three rats at 15 minutes after the intravenous administration of 3H-MK-801, the level (mean ± standard error of the mean) of isotopic tracer in the ischemic cortex and striatum was markedly less than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 22 ± 4 vs. 84 ± 11 pmol/gm, p < 0.01). In contrast, in a group of five rats at 60 minutes after the intravenous administration of 3H-MK-801, the level of isotopic tracer in the ischemic cortex and striatum was greater than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 52 ± 8 vs. 32 ± 4 pmol/gm, p < 0.05). There were no significant alterations in the specific binding of 3H-MK-801 in vitro in ischemic tissue at equivalent times. The early uptake of 3H-MK-801 into the central nervous system is dominated by the level of cerebral blood flow, whereas at later times after administration enhancement of MK-801 binding by elevated extracellular glutamate concentrations appears to be more important in determining the level of the drug in ischemic tissue.

Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).

1995 ◽  
Vol 198 (7) ◽  
pp. 1621-1628 ◽  
Author(s):  
L T Buck ◽  
P E Bickler
Keyword(s):  
Cerebral Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Control Level ◽  
Chrysemys Picta ◽  
Receptor Modulation ◽  
A1 Receptor ◽  
Excitatory Neurotransmission ◽  
Similar Decrease

Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.

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