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, 28 (6), 697-708

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

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

Darine Froy N Mabunga et al. Exp Neurobiol.

Abstract

Despite some innate limitations, animal models are a potent investigative tool when used to model specific symptoms of a disorder. For example, MK-801, an N-methyl-D-aspartate receptor antagonist, is used as a pharmacological tool to induce symptoms found in some neuropsychiatric disorders. However, a close examination of literature suggests that the application window of MK-801 doses is relatively narrow between individual behavioral paradigms, necessitating careful characterization of the evoked behavioral aberrations and the doses used to induce them. Moreover, variation in behaviors depending on the animal strain, gender of the subject, and the timing of administration is observed, making it difficult to compare the behavioral characteristics reported in different studies. We aim to characterize the behavioral aberrations induced by different doses of MK-801 in CD-1 mice and create a ready reference for future studies. We used CD-1 mice to recapitulate behavioral impairments resulting from acute administration of MK-801. In 0.1 mg kg-1, we observed diminished spontaneous alteration during the Y-maze test, while 0.12 mg kg-1 resulted in hyperlocomotion and social deficit. Mice treated with 0.2 and 0.3 mg kg-1 of MK-801 demonstrated a decreased self-grooming. Finally, all doses significantly impaired cliff avoidance behaviors suggesting increased impulsivity. These results affirm that MK-801 can effectively model various symptoms of different neuropsychiatric disorders in a dose-dependent manner. The observed sensitivity against spatial-memory impairment and impulsive behaviors at low concentration of MK-801 suggest that MK801 may modulate cognitive function and impulsivity in even lower concentration before it can modulate other behavioral domains.

Keywords: Animal model; Behavioral domains; MK-801; Neuropsychiatric disorders.

Figures

Fig. 1
Fig. 1
Experimental scheme. Mice were allowed to habituate for five days in the designated animal facility. On the day of the experiment, MK-801 and saline were given 30 minutes prior to the test.
Fig. 2
Fig. 2
Effects of MK-801 administration on locomotor activity of mice in the open field test. Subject mice were administered with either MK-801 (0.1, 0.12, 0.15, 0.2 and 0.3 mg kg−1) or 0.9% NaCl thirty minutes prior to the experiment. Open field test was then performed for 25 minutes, measuring the distance moved (Fig. 2A) and its progression in a five-minute time bin (Fig. 2B) as parameters. Data were analyzed using a one-way ANOVA test and are expressed as the mean±S.E.M (n=10~15 mice per group). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. vehicle group as revealed by post hoc Tukey's multiple comparisons test.
Fig. 3
Fig. 3
Effects of MK-801 administration on spontaneous alternation and total arm entries of mice in Y-maze. Y-maze was performed on mice thirty minutes after they were administered with either MK-801 (0.1, 0.12, 0.15, 0.2 and 0.3 mg kg−1) or 0.9% NaCl. Parameters measured were the percentage of spontaneous alternations (Fig. 3A) and the total number of arm entries (Fig. 3B). All data are expressed as the mean±S.E.M (n=10~20 mice per group). ***p<0.001, ****p<0.0001 vs. vehicle group as revealed by post hoc Tukey's multiple comparisons test.
Fig. 4
Fig. 4
Effects of MK-801 administration on social behaviors of mice in the three-chamber social assay. Subject mice were administered with either MK-801 (0.1, 0.12, 0.15, 0.2 and 0.3 mg kg−1) or 0.9% NaCl thirty minutes prior to performing three-chamber social assay. Fig. 4A shows the effects of MK-801 on the stay duration of mice in the stranger, center, and empty sides. The chamber preference index for the social interaction phase was then calculated as described in the Materials and Methods section and is shown in Fig. 4B. Figs. 4C and 3D demonstrate the effects of MK-801 on the social preference phase. All data are expressed as the mean±S.E.M (n=15~20 mice per group). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. vehicle group as revealed by post hoc Tukey's multiple comparisons test.
Fig. 5
Fig. 5
Effects of MK-801 administration on the self-grooming behavior of mice. Subject mice were administered with either MK-801 (0.1, 0.12, 0.15, 0.2 and 0.3 mg kg−1) or 0.9% NaCl thirty minutes prior to the observation of self-grooming behavior. The total time spent self-grooming was then measured and recorded. All data expressed as the mean±S.E.M (n=14~15 mice per group). *p<0.05, ****p<0.0001 vs. Vehicle group as revealed by post hoc Tukey's multiple comparisons test.
Fig. 6
Fig. 6
Effects of MK-801 administration on cliff avoidance reaction of mice in the cliff-avoidance test. Cliff avoidance test was performed on mice thirty minutes after they were administered with either MK-801 (0.1, 0.12, 0.15, 0.2 and 0.3 mg kg−1) or 0.9% NaCl, with CJE in a 1-min time bin (Fig. 6A) and jumping latency (Fig. 6B) as parameters measured. All data are expressed as the mean±S.E.M (n=10 mice per group). *p<0.05, ***p<0.001, ****p<0.0001 vs. vehicle group as revealed by post hoc Tukey's multiple comparisons test and Chi-square analysis test.

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