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.

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.

Corrigendum: 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.

[This corrects the article on p. 75 in vol. 9, PMID: 25883558.].

Comparison of Long-Evans and Wistar rats in sensitivity to central cholinergic blockade with scopolamine in two spatial tasks: an active place avoidance and the Morris water maze.

Place navigation is essential for an animal's survival and this behavior has attracted the attention of scientists focused on the neural and neuropharmacological bases of learning and memory. Many navigational tests are employed today, such as the Morris water maze (MWM) which demands a precise representation of an unmarked place. Another spatial paradigm is the active place avoidance task. It requires mainly cognitive coordination in contrast to the MWM. Various rat strains are used in the research of animal models of cognitive impairments. The aim of this study was to compare sensitivity to the administration of higher doses (1.5mg/kg and 3mg/kg) of the central cholinergic blocker, scopolamine in outbred Long-Evans and Wistar rats. The results showed that while Wistar rats were more strongly affected by cholinergic blockade in the active place avoidance than Long-Evans rats, no differences were seen in the MWM. Long-Evans rats also showed better baseline performance in the active place avoidance and visible platform versions of the MWM (the latter suggesting better vision). This study demonstrated task-specific inter-strain differences in sensitivity to central cholinergic blockade in an active place avoidance task requiring cognitive coordination.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study.

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10-0.15 mgkg(-1). Some impairment was observed in the active place avoidance task at 0.08 mgkg(-1). Swimming towards a visible platform was impaired only by the highest dose (0.15 mgkg(-1)). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.