Higher Doses of (+)MK-801 (Dizocilpine) Induced Mortality and Procedural but Not Cognitive Deficits in Delayed Testing in the Active Place Avoidance With Reversal on the Carousel

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute’s breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

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Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

Neuroscience Research ◽

10.1016/j.neures.2006.04.007 ◽

2006 ◽

Vol 55 (4) ◽

pp. 383-388 ◽

Cited By ~ 34

Author(s):

Karel Vales ◽

Vera Bubenikova-Valesova ◽

Daniel Klement ◽

Ales Stuchlik

Keyword(s):

Working Memory ◽

Morris Water Maze ◽

Water Maze ◽

Wistar Rats ◽

Avoidance Task ◽

Mk 801 ◽

Place Avoidance ◽

Long Evans

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Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

10.1101/152488 ◽

2017 ◽

Author(s):

Dino Dvorak ◽

Basma Radwan ◽

Fraser T. Sparks ◽

Zoe Nicole Talbot ◽

André A. Fenton

Keyword(s):

Fragile X Syndrome ◽

Cognitive Deficits ◽

Pyramidal Cell ◽

Fragile X ◽

Avoidance Task ◽

Cognitive Variables ◽

Wild Type ◽

Cognitive Inflexibility ◽

Place Avoidance ◽

Shock Zone

ABSTRACTBehavior is used to assess memory and cognitive deficits in animals like Fmrl-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal CA1 hippocampus. During a shocked-place avoidance task, slow gamma (SG: 30-50 Hz) dominates mid-frequency gamma (MG: 70-90 Hz) oscillations 2-3 seconds before successful avoidance, but not failures. Wild-type but not Fmrl-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdominance) decrease in wild-type but not in cognitively inflexible Fmrl-null mice. During SGdominance, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, wild-type ensembles represent distant locations near the currently-correct shock zone but Fmrl-null ensembles represent the formerly-correct zone. These findings indicate that recollection occurs when CA1 slow gamma dominates mid-frequency gamma, and that accurate recollection of inappropriate memories explains Fmrl-null cognitive inflexibility.

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Effect of alpha1-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats

Physiological Research ◽

10.33549/physiolres.931636 ◽

2009 ◽

pp. 733-740

Author(s):

A Stuchlík ◽

T Petrásek ◽

K Valeš

Keyword(s):

Memory Task ◽

Psychotic Symptoms ◽

Behavioral Alterations ◽

Cognitive Changes ◽

Mk 801 ◽

Locomotor Stimulation ◽

Adrenergic Antagonist ◽

Place Avoidance ◽

Higher Doses

Animal models of neuropsychiatric disorders are current topics in behavioral neuroscience. Application of non-competitive antagonists of NMDA receptors (such as MK-801) was proposed as a model of schizophrenia, as it leads to specific behavioral alterations, which are partly analogous to human psychotic symptoms. This study examined an animal model of schizophrenia induced by a systemic application of MK-801 (0.15 and 0.20 mg/kg) into rats tested in the active allothetic place avoidance (AAPA) task. Previous studies suggested that MK-801 may interact in vivo with other neurotransmitter systems, including noradrenergic system. Our experiments therefore evaluated the hypothesis that both locomotor stimulation and deficit in avoidance behavior in AAPA task induced by this drug would be reversible by application of alpha1-adrenergic antagonist prazosin (1 and 2 mg/kg). The results showed that both doses of prazosin partially reversed hyperlocomotion induced by higher doses of MK-801 and an avoidance deficit measured as number of entrances into the shock sector. Interestingly, no effect of prazosin on the MK-801-induced decrease of maximum time between two entrances (another measure of cognitive performance) was observed. These results support previous data showing that prazosin can compensate for the hyperlocomotion induced by MK-801 and newly show that this partial reduction sustains even in the forced locomotor conditions, which are involved in the AAPA task. The study also shows that certain parameters of avoidance efficiency may be closely related to locomotor activity, whereas other measures of cognition may more selectively reflect cognitive changes.

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Transient Inactivation of the Medial Prefrontal Cortex and Ventral Hippocampus Impairs Active Place Avoidance Retrieval on a Rotating Arena

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.634533 ◽

2021 ◽

Vol 15 ◽

Author(s):

Daniela Cernotova ◽

Ales Stuchlik ◽

Jan Svoboda

Keyword(s):

Prefrontal Cortex ◽

Spatial Memory ◽

Medial Prefrontal Cortex ◽

Ventral Hippocampus ◽

Avoidance Task ◽

Exact Role ◽

Spatial Coordination ◽

Place Avoidance ◽

Long Evans

It is well known that communication between the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC) is critical for various cognitive and behavioral functions. However, the exact role of these structures in spatial coordination remains to be clarified. Here we sought to determine the involvement of the mPFC and the vHPC in the spatial retrieval of a previously learned active place avoidance task in adult male Long-Evans rats, using a combination of unilateral and bilateral local muscimol inactivations. Moreover, we tested the role of the vHPC-mPFC pathway by performing combined ipsilateral and contralateral inactivations. Our results showed not only bilateral inactivations of either structure, but also the combined inactivations impaired the retrieval of spatial memory, whereas unilateral one-structure inactivations did not yield any effect. Remarkably, muscimol injections in combined groups exerted similar deficits, regardless of whether the inactivations were contralateral or ipsilateral. These findings confirm the importance of these structures in spatial cognition and emphasize the importance of the intact functioning of the vHPC-mPFC pathway.

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Dizocilpine (MK-801) impairs learning in the active place avoidance task but has no effect on the performance during task/context alternation

Behavioural Brain Research ◽

10.1016/j.bbr.2016.03.020 ◽

2016 ◽

Vol 305 ◽

pp. 247-257 ◽

Cited By ~ 2

Author(s):

Iveta Vojtechova ◽

Tomas Petrasek ◽

Hana Hatalova ◽

Adela Pistikova ◽

Karel Vales ◽

...

Keyword(s):

Avoidance Task ◽

Task Context ◽

Mk 801 ◽

Place Avoidance

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Effect of Vasopressin Dose on Hemodynamic Response in Obese Patients With Septic Shock: A Retrospective Observational Study

Annals of Pharmacotherapy ◽

10.1177/10600280211007213 ◽

2021 ◽

pp. 106002802110072

Author(s):

Casey A. Dubrawka ◽

Kevin D. Betthauser ◽

Hannah E. Pope ◽

Gabrielle A. Gibson

Keyword(s):

Septic Shock ◽

Retrospective Cohort ◽

Primary Outcome ◽

Standard Dose ◽

Hemodynamic Response ◽

Percentage Change ◽

High Dose ◽

Obese Patients ◽

Improved Outcomes ◽

Higher Doses

Background No clear association between standard vasopressin doses and body mass index exists, despite potential pharmacokinetic and pharmacodynamic variability among patients with septic shock. It is unknown if higher doses may alter hemodynamic response. Objective The purpose of this study was to evaluate the effect of vasopressin dose on hemodynamic response in obese patients with septic shock. Methods A single-center, retrospective cohort study was conducted in adult, obese patients with septic shock receiving catecholamine vasopressors and vasopressin. Patients were analyzed according to vasopressin dose received: standard dose (≤0.04 U/min) and high dose (>0.04 U/min). The primary outcome was percentage change in norepinephrine equivalent (NEQ) dose. Results A total of 182 patients were included in the analysis, with 136 in the standard-dose vasopressin group and 46 in the high-dose vasopressin group. There was no difference in percentage change in NEQ dose at 6 hours after standard- or high-dose vasopressin attainment (−28.6% vs −19.1%; P = 0.166). A greater increase in mean arterial pressure (MAP) at 6 hours was observed with receipt of high-dose vasopressin (23.3% vs 15.3%; P = 0.023). Duration of shock and length of stay were significantly longer in patients who received high-dose vasopressin, with no difference in in-hospital mortality. Conclusion and Relevance This represents the first analysis comparing standard and higher doses of vasopressin in obese patients with septic shock. Receipt of high-dose vasopressin was not associated with a difference in catecholamine requirement or improved outcomes. Further studies are warranted to provide guidance on the use of high-dose vasopressin in septic shock.

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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 ◽

10.3390/biom11071026 ◽

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.

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Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

Dose-Response ◽

10.1177/1559325820982166 ◽

2021 ◽

Vol 19 (1) ◽

pp. 155932582098216

Author(s):

Bing Wang ◽

Kaoru Tanaka ◽

Takanori Katsube ◽

Kouichi Maruyama ◽

Yasuharu Ninomiya ◽

...

Keyword(s):

Dietary Restriction ◽

High Dose ◽

Cancer Treatments ◽

Hematopoietic Stem ◽

Beneficial Effects ◽

Radiation Induced ◽

Potential Strategy ◽

Higher Doses

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

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Effect of Energy and Dose on Transient-Enhanced Diffusion and Defect Microstructure in Low Energy High Dose As+ Implanted Si

MRS Proceedings ◽

10.1557/proc-438-21 ◽

1996 ◽

Vol 438 ◽

Author(s):

V. Krishnamoorthy ◽

D. Venables ◽

K. Moeller ◽

K. S. Jones ◽

B. Freer

Keyword(s):

Point Defects ◽

Surface Recombination ◽

High Dose ◽

Enhanced Diffusion ◽

Projected Range ◽

Diffusion Enhancement ◽

Defect Microstructures ◽

Dose Dependent ◽

Higher Doses ◽

Defect Microstructure

Abstract(001) CZ silicon wafers were implanted with arsenic (As+) at energies of 10–50keV to doses of 2×1014 to 5×1015/cm2. All implants were amorphizing in nature. The samples were annealed at 700°C for 16hrs. The resultant defect microstructures were analyzed by XTEM and PTEM and the As profiles were analyzed by SIMS. The As profiles showed significantly enhanced diffusion in all of the annealed specimens. The diffusion enhancement was both energy and dose dependent. The lowest dose implant/annealed samples did not show As clustering which translated to a lack of defects at the projected range. At higher doses, however, projected range defects were clearly observed, presumably due to interstitials generated during As clustering. The extent of enhancement in diffusion and its relation to the defect microstructure is explained by a combination of factors including surface recombination of point defects, As precipitation, As clustering and end of range damage.

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