Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats

Savolainen, Katja; Ihalainen, Jouni; Hämäläinen, Elina; Tanila, Heikki; Forsberg, Markus

doi:10.1016/j.bbr.2020.113057

Cited by 6 publications

(4 citation statements)

References 64 publications

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“…To identify neuronal substrates supporting flexible choice in preclinical species, PRL tasks are often paired with a pharmacological challenge to model cognitive impairments observed in patients. For example, the NMDA receptor antagonist dizocilpine (MK-801) is known to induce cognitive deficits, impair reversal learning in rodents (van der Meulen et al, 2003;Dix et al, 2010;Svoboda et al, 2015;Savolainen et al, 2021), and induce c-Fos expression in brain areas implicated in the pathophysiology of schizophrenia (Dragunow and Faull, 1990;Väisänen et al, 2004). Reversible inactivation or lesion of brain areas has identified neural circuits that support cognitive flexibility in PRL tasks (Stalnaker et al, 2007;Rudebeck and Murray, 2008;Izquierdo et al, 2013;Dalton et al, 2016;Nakayama et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task

et al. 2022

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Cognitive flexibility, the ability to adapt to unexpected changes, is critical for healthy environmental and social interactions, and thus to everyday functioning. In neuropsychiatric diseases, cognitive flexibility is often impaired and treatment options are lacking. Probabilistic reversal learning (PRL) is commonly used to measure cognitive flexibility in rodents and humans. In PRL tasks, subjects must sample choice options and, from probabilistic feedback, find the current best choice which then changes without warning. However, in rodents, pharmacological models of human cognitive impairment tend to disrupt only the first (or few) of several contingency reversals, making quantitative assessment of behavioral effects difficult. To address this limitation, we developed a novel rat PRL where reversals occur at relatively long intervals in time that demonstrates increased sensitivity to the non-competitive NMDA receptor antagonist MK-801. Here, we quantitively compare behavior in time-based PRL with a widely used task where reversals occur based on choice behavior. In time-based PRL, MK-801 induced sustained reversal learning deficits both in time and across reversal blocks but, at the same dose, only transient weak effects in performance-based PRL. Moreover, time-based PRL yielded better estimates of behavior and reinforcement learning model parameters, which opens meaningful pharmacological windows to efficiently test and develop novel drugs preclinically with the goal of improving cognitive impairment in human patients.

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Section: Introductionmentioning

confidence: 99%

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task

et al. 2022

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“…Indeed, one study showed that subchronic ketamine (30 mg/kg once daily for 5 consecutive days) was sufficient to increase striatal dopamine synthesis and locomotor activity in mice (Kokkinou et al, 2021). Another study reported that subchronic PCP (1.5 mg/kg once daily for 4 days) impaired reversal learning in rats without affecting other nonspecific behaviors (Savolainen et al, 2021). Counterbalancing behavioral tests might account for some of the nonspecific effects of repeated exposure to drugs.…”

Section: Discussionmentioning

confidence: 99%

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis‐like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia‐relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia‐relevant NMDAR antagonist‐induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia‐relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S‐ketamine enantiomer (S‐ket), and the ketamine metabolite R‐norketamine (R‐norket) on locomotor activity, anxiety‐related behavior, and recognition and short‐term spatial memory. GluN2D‐KO mice showed a blunted locomotor response to R‐norket, S‐ket, and PCP, a phenotype present in both sexes. GluN2D‐KO mice of both sexes showed an anxious phenotype and S‐ket, R‐norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S‐ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex‐specific effects of NMDAR antagonists and on the differential effects of the R‐ and S‐ket enantiomers.

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“…The set-shifting paradigm is considered as ethologically appropriate, as it is analogous to the extended Wisconsin card sorting test but relies on olfaction or somatosensation and digging instead of vision and depends on the activity of the medial prefrontal cortex (Birrell and Brown 2000). The development of touchscreen technology, involving paradigms such as pairwise visual discrimination and reversal learning, allows for assessing behavioral flexibility in rodents and creates more complex and challenging tasks with improved reproducibility (Savolainen et al 2021). In this method, the animal responds to the presented visual stimuli through a screen nose poke (Bussey et al 2008).…”

Section: Mk-801 and Cognitive Flexibilitymentioning

confidence: 99%

“…Moreover, optogenetic stimulation of parvalbumin-positive interneurons in the prefrontal cortex and hippocampus rescued the performance (Patrono et al 2023). Alternative often-used task to assess cognitive flexibility in rodents is the probabilistic reversal learning task (Bartolo and Averbeck 2020;Savolainen et al 2021). In the study of Latuske et al (2022), this paradigm was modified to include two distinct parts: performance-based probabilistic reversal learning (representing the standard version of the task) and time-based probabilistic reversal learning.…”

Section: Mk-801 and Cognitive Flexibilitymentioning

confidence: 99%

MK-801 and cognitive functions: Investigating the behavioral effects of a non-competitive NMDA receptor antagonist

Janus,

Lustyk,

Pytka

2023

Psychopharmacology

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Rationale MK-801 (dizocilpine) is a non-competitive NMDA receptor antagonist originally explored for anticonvulsant potential. Despite its original purpose, its amnestic properties led to the development of pivotal models of various cognitive impairments widely employed in research and greatly impacting scientific progress. MK-801 offers several advantages; however, it also presents drawbacks, including inducing dose-dependent hyperlocomotion or ambiguous effects on anxiety, which can impact the interpretation of behavioral research results. Objectives The present review attempts to summarize and discuss the effects of MK-801 on different types of memory and cognitive functions in animal studies. Results A plethora of behavioral research suggests that MK-801 can detrimentally impact cognitive functions. The specific effect of this compound is influenced by variables including developmental stage, gender, species, strain, and, crucially, the administered dose. Notably, when considering the undesirable effects of MK-801, doses up to 0.1 mg/kg were found not to induce stereotypy or hyperlocomotion. Conclusion Dizocilpine continues to be of significant importance in preclinical research, facilitating the exploration of various procognitive therapeutic agents. However, given its potential undesirable effects, it is imperative to meticulously determine the appropriate dosages and conduct supplementary evaluations for any undesirable outcomes, which could complicate the interpretation of the findings.

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Phencyclidine-induced cognitive impairments in repeated touchscreen visual reversal learning tests in rats

Cited by 6 publications

References 64 publications

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

MK-801 and cognitive functions: Investigating the behavioral effects of a non-competitive NMDA receptor antagonist

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