Acute administration of MK-801 in an animal model of psychosis in rats interferes with cognitively demanding forms of behavioral flexibility on a rotating arena

Abstract

Patients with schizophrenia often manifest deficits in behavioral flexibility. Non-competitive NMDA receptor antagonists such as MK-801 induce schizophrenia-like symptoms in rodents, including cognitive functions. Despite work exploring flexibility has been done employing behavioral paradigms with simple stimuli, much less is known about what kinds of flexibility are affected in an MK-801 model of schizophrenia-like behavior in the spatial domain. We used a rotating arena-based apparatus (Carousel) requiring rats to avoid an unmarked sector defined in either the reference frame of the rotating arena (arena frame task, AF) or the stationary room (room frame task, RF). We investigated behavioral flexibility in four conditions involving different cognitive loads. Each condition encompassed an initial (five sessions) and a test phase (five sessions) in which some aspects of the task were changed to test flexibility and in which rats were given saline, 0.05 mg/kg or 0.1 mg/kg MK-801 thirty minutes prior to a session. In the first condition, rats acquired avoidance in RF with clockwise rotation of the arena while in the test phase the arena rotated counterclockwise. In the second condition, rats initially acquired avoidance in RF with the sector on the north and then it was reversed to south (spatial reversal). In the third and fourth conditions, rats initially performed an AF (RF, respectively) task, followed by an RF (AF, respectively) task, testing the ability of cognitive set-shifting. We found no effect of MK-801 either on simple motor adjustment after reversal of arena rotation or on spatial reversal within the RF. In contrast, administration of MK-801 at a dose of 0.1 mg/kg interfered with set-shifting in both conditions. Furthermore, we observed MK-801 0.1 mg/kg elevated locomotion in all cases. These data suggest that blockade of NMDA receptors by acute system administration of MK-801 preferentially affects set-shifting in the cognitive domain rather than reversal.

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits

“…Importantly, marked disruptions of behavioral functions similar to those found in schizophrenia can be induced in animal models using acute application of MK-801, a prototypical experimental high-affinity non-competitive antagonist of NMDA receptors. These include social deficits (low doses; Rung et al, 2005 ), cognitive deficits (low-to-moderate doses; van der Staay et al, 2011 ; Lobellova et al, 2013 , Kubík et al, 2014 ; Svoboda et al, 2015 ) and toxic and experimental psychoses (higher doses, Vales et al, 2006 ; Lobellová et al, 2015 ). Chronic experiments aimed at mimicking the neurodevelopmental abnormalities have shown that these manipulations can also induce schizophrenia-like behaviors.…”

The neural basis of reversal learning: An updated perspective

“…Consequently, a number of investigators have examined the role of the NMDAR, as well as other glutamate receptors and transporters (Karlsson et al, 2009, Barkus et al, 2012), in reversal learning and other forms of cognitive flexibility (for review, see (Jentsch and Roth, 1999). This work has led to reports that acute, systemic NMDAR blockade (with MK-801) can cause impairments in spatial reversal learning (Lobellova et al, 2013), but also fail to affect reversal performance and instead disrupt set-shifting (Svoboda et al, 2015). The literature on the effects of subchronic NMDAR antagonism with phencyclidine (PCP) (considered a potential model of schizophrenia (Brigman et al, 2010a) is also equivocal.…”

Recapitulation of Neuropsychiatric Behavioral Features in Mice Using Acute Low-dose MK-801 Administration

“…MK-801, or dizocilpine, a N-methyl-D-aspartate receptor (NM-DAR) antagonist, was first used as a pharmacologic model of psychosis in rats in 1999 [6] and is still widely utilized as a model for symptoms observed in schizophrenia. MK-801 may not be able to model schizophrenia in its entirety but it can mimic particular cognitive deficits such as behavioral inflexibility [7], impaired spatial memory (reviewed in [8]), and social withdrawal [9]. However, the use of MK-801 as a pharmacological model should not be limited to the symptoms of schizophrenia, considering the complexity and the multiple overlapping domains of neuropsychiatric disorders in humans [10,11].…”