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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

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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

Jan Svoboda et al. Front Behav Neurosci.

Erratum in

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.

Keywords: Carousel; MK-801; cognitive flexibility; rat; reversal; schizophrenia; set-shifting.

Figures

Figure 1
Figure 1
Scheme of behavioral protocol of all four conditions employed. Note that injections (saline or MK-801) were applied only prior to sessions in the test phase. To indicate mutual relationship of the sector and the rotating arena in each condition, position of an immobile rat and the to-be-avoided sector is shown for a time t at the beginning of the session (thin outlines) and t + 15 s (bold outlines). Note that the position of the sector remains fixed during the Room frame avoidance but rotates during the Arena frame avoidance.
Figure 2
Figure 2
Performance of the rats in condition 1 (motor response switch). Upper graph indicates total path elapsed during the last session of the initial phase, first session of the test phase, and its split into two 10 min segments (group means ± SEM). Lower graph shows proportion of session time spent in the prohibited sector. Difference between the session 1 of the test phase and the session 5 of the initial phase were computed as difference scores and the resulting statistics is provided. * P < 0.05 compared to saline group.
Figure 3
Figure 3
Performance of the rats in condition 2 (reversal within RF). Upper graph indicates total path elapsed during the last session of the initial phase, first session of the test phase, and its split into two 10 min segments (group means ± SEM). Lower graph shows proportion of session time spent in the prohibited sector. Difference between the session 1 of the test phase and the session 5 of the initial phase were computed as difference scores and the resulting statistics is provided. * P < 0.05 compared to saline group.
Figure 4
Figure 4
Performance of the rats in condition 3 (set shifting: AF to RF switch). Upper graph indicates total path elapsed during the last session of the initial phase, first session of the test phase, and its split into two 10 min segments (group means ± SEM). Lower graph shows proportion of session time spent in the prohibited sector. Difference between the session 1 of the test phase and the session 5 of the initial phase were computed as difference scores and the resulting statistics is provided. * P < 0.05 compared to saline group. Difference in time spent in the sector between MK-801 0.1 mg/kg and saline group was found significant when a two-way ANOVA was conducted on the whole test phase and Tukey’s post hoc test applied on significant MK-801 × SESSION interaction. However, this difference was not considered significant when using difference scores.
Figure 5
Figure 5
Performance of the rats in condition 4 (set shifting: RF to AF switch). Upper graph indicates total path elapsed during the last session of the initial phase, first session of the test phase, and its split into two 10 min segments (group means ± SEM). Lower graph shows proportion of session time spent in the prohibited sector. Difference between the session 1 of the test phase and the session 5 of the initial phase were computed as difference scores and the resulting statistics is provided. * P < 0.05, ** P < 0.01, *** P < 0.001 compared to saline group.

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