Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation

Kumar, Gaurav; Olley, Joseph; Steckler, Thomas; Talpos, John C.

doi:10.1007/s00213-015-4008-9

Cited by 32 publications

(51 citation statements)

References 44 publications

(68 reference statements)

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“…Similarly, non-competitive NMDA receptor antagonism in rodents produces behaviors analogous to the positive, negative, and cognitive symptoms of schizophrenia (Moghaddam and Krystal 2012). For example, locomotor hyperactivity (Manahan-Vaughan et al 2008;Howland et al 2012;Zemanova et al 2013;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on visual learning and working memory tasks (Brown et al 2013;Zemanova et al 2013;Kumar et al 2015b;Kumar et al 2015a;Lins and Howland 2016) are observed following MK-801 administration, mirroring the positive, negative, and cognitive symptoms respectively. Beyond its direct effect on NMDA receptors, MK-801 administration indirectly mimics other pathophysiological features of the disease (Lewis et al 2005).…”

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

“…Thus, the first objective of this research is to demonstrate the face validity of the MK-801 model of schizophrenia in the TUNL task. Only one previous study has investigated performance changes following acute MK-801 administration in the TUNL task (Kumar et al 2015a). The results of this experiment showed 0.05 mg/kg of MK-801 impaired task accuracy with 1 s and 20 s delays.…”

Section: Rationale and Hypothesesmentioning

confidence: 99%

“…The high cross-species translatability of this task makes it a promising and unique platform to study potential treatment of cognitive impairment in schizophrenia (Bussey et al 2012). To date, only one experiment has examined task performance in a rodent model of schizophrenia (Kumar et al 2015a) and none have attempted to reverse any observed impairments.…”

Section: Introductionmentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

Section: Rationale and Hypothesesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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“…First, these tasks were applied in rats in some studies (Talpos et al 2014;Kumar et al 2015). The dPAL task was shown to be sensitive to pharmacological inhibition of hippocampal activity (Talpos et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The dPAL task was shown to be sensitive to pharmacological inhibition of hippocampal activity (Talpos et al 2009). In addition, this task was used to test the effect of antagonism of various Nmethyl-d-aspartate receptor subtypes in rats (Kumar et al 2015). The PAL task has also been used in mice in various studies (Bartko et al 2011b;Delotterie et al 2015;Kim et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Optimization of the touchscreen paired-associate learning (PAL) task for mice and its dorsal hippocampal dependency

Kim

Kwak

et al. 2016

Animal Cells and Systems

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Two versions of the touchscreen paired-associate learning (PAL) task have been developed for rodents: same PAL (sPAL) and different PAL (dPAL). These tasks are very important in studying murine models of Alzheimer's disease and schizophrenia, and have also been used to test object-location memory in various studies. However, the relatively long time needed for the tasks (approx. 50 days for mice) limits their widespread use. By giving training that was more intensive with a higher number of trials, we shortened the time required for learning saturation in sPAL and dPAL to about one-third of the time required for the generally used protocol. Furthermore, by applying a reduced number of objects and trial types for sPAL, we developed a simplified version of sPAL, termed 2-object sPAL, in which mice could reach the fully learned level in 6 days. Our pharmacological experiments indicate that the dorsal hippocampal CA1 region is crucial for the performance of the two PAL tasks with the new protocols and the new 2-object sPAL. This work has significantly enhanced the usefulness of the touchscreen PAL tasks to increase the speed of learning, but they remain highly hippocampus-dependent objectlocation memory tasks. ARTICLE HISTORY

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Antipsychotic Agents

Ablordeppey

Ofori

2021

Burger's Medicinal Chemistry and Drug Discovery

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Schizophrenia is one of the most severe diseases of the brain and is characterized by a spectrum of symptoms including positive, negative, and cognitive symptoms. Even though schizophrenia has a low worldwide prevalence (0.4–0.7%), it is one of the most devastating diseases of the central nervous system (CNS). Despite the immense studies on schizophrenia over the years, the exact cause of the disorder remains unknown. Therefore, morbidity studies and their outcomes for schizophrenia continue to rely on descriptive definitions spelled out in the Diagnostic and Statistical Manual of Mental Disorders‐fifth edition (DSM‐5). Current pharmacotherapy of the disease involves the use of antipsychotic agents that target CNS receptors including dopamine and serotonin receptor subtypes. Despite the success in the management of psychiatric illness most of the current antipsychotics are saddled with problems such as inefficacy across patient populations and disease domains and intolerable side effects that limit their widespread utility. Evolving paradigm shift in antipsychotic drug discovery efforts over the last decade has begun to address these issues opening the door for new hypotheses that integrate well‐known neurotransmitter systems with neuronal circuits. Recent advances in molecular biology and genetics are also paving the way for a better understanding of the etiology and pathophysiology of schizophrenia. In addition to reviewing currently used agents, this article will focus on the advances made to address the stated problems and highlight the paradigm shift in the antipsychotic drug discovery area.

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Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation

Abstract: These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

Cited by 32 publications

References 44 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

Optimization of the touchscreen paired-associate learning (PAL) task for mice and its dorsal hippocampal dependency

Antipsychotic Agents

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