1MeTIQ and olanzapine, despite their neurochemical impact, did not ameliorate performance in fear conditioning and social interaction tests in an MK-801 rat model of schizophrenia

Abstract

Background: The aim of the present study was to evaluate the effect of 1MeTIQ on fear memory and social interaction in an MK-801-induced model of schizophrenia. The results obtained after administration of 1MeTIQ were compared with those obtained with olanzapine, an antipsychotic drug.

Methods: Sprague-Dawley rats received a single injection of MK-801 to induce behavioral disorders. 1MeTIQ was given either acutely in a single dose or chronically for 7 consecutive days. Olanzapine was administered once. In groups receiving combined treatments, 1MeTIQ or olanzapine was administered 20 min before MK-801 injection. Contextual fear conditioning was used to assess disturbances in fear memory (FM), and the sociability of the rats was measured in the social interaction test (SIT). Biochemical analysis was carried out to evaluate monoamine levels in selected brain structures after treatment.

Results: Our results are focused mainly on data obtained from neurochemical studies, demonstrating that 1MeTIQ inhibited the MK-801-induced reduction in dopamine levels in the frontal cortex and increased the 5-HT concentration. The behavioral tests revealed that acute administration of MK-801 caused disturbances in both the FM and SIT tests, while neither 1MeTIQ nor olanzapine reversed these deficits.

Conclusion: 1MeTIQ, although pharmacologically effective (i.e., it reverses MK-801-induced changes in monoamine activity), did not influence MK-801-induced social and cognitive deficits. Thus, our FM tests and SIT did not support the main pharmacological hypotheses that focus on dopamine system stabilization and dopamine-serotonin system interactions as probable mechanisms for inhibiting the negative symptoms of schizophrenia.

Keywords: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ); Contextual fear conditioning; MK-801; Neurochemical studies; Olanzapine; Social interaction test (SIT).

Fig. 1

Schematic representation of the FM experiment. Chronic treatment with 1MeTIQ lasted for 7 days, and the last dose was given on the day of the experiment 20 min before MK-801. The FM test consisted of the acquisition/training phase in Context A (day 1) and the testing phase in Context A—CFC and Context B—AFC (day 2). The interval between CFC and AFC on day 2 lasted 2 h. N = 8–10 rats per group. After behavioral testing, animals were immediately decapitated

Fig. 2

Schematic representation of the SIT. Chronic treatment with 1MeTIQ lasted for 7 days, and the last dose was given on the day of the experiment 30 min after MK-801 and 210 min before behavioral testing. The SIT consisted of habituation and general testing with a 24-h intervening interval. N = 8–10 rats per group. Immediately after the test, animals were decapitated

Fig. 3

The effect of MK-801 (0.3 mg/kg, sc), acute 1MeTIQ (25 mg/kg, ip) and olanzapine (3 mg/kg, ip) administration on the expression of fear conditioning in the forms of CFC (a) and AFC b in the testing phase (day 2). The data were analyzed using one-way ANOVA and a post hoc Duncan’s MRT. The data are shown as the means ± SEM and expressed as a percentage of the session time. N = 8–10 rats per group. *p < 0.05; **p < 0.01; ***p < 0.001 compared to the control (saline) group. Significant changes were not observed when compared to the MK-801-treated group

Fig. 4

The effect of MK-801 (0.3 mg/kg, sc) and chronic (7x) 1MeTIQ (25 mg/kg, ip) administration on the expression of fear conditioning in the forms of CFC (a) and AFC b in the testing phase (day 2). The data were analyzed using two-way ANOVA and a post hoc Duncan’s MRT. The data are shown as the means ± SEM and expressed as a percentage of the session time. N = 8–10 rats per group. *p < 0.05; **p < 0.01; ***p < 0.001 compared to the control (SAL) group. Significant changes were not observed when compared to the MK-801-treated group

Fig. 5

The effect of MK-801 (0.3 mg/kg, sc), acute 1MeTIQ (25 mg/kg, ip) and olanzapine (3 mg/kg, ip) administration on the duration of social interaction (a) and number of social interactions b in the SIT. The data were analyzed using one-way ANOVA and a post hoc Duncan’s MRT. The data are shown as the means ± SEM. N = 8–10 rats per group. *p < 0.05; **p < 0.01; ***p < 0.001 compared to the control (SAL) group. ^#p < 0.05; ^##p < 0.01; ^###p < 0.001 when compared to the MK-801-treated group

Fig. 6

The effect of MK-801 (0.3 mg/kg, sc) and chronic (7x) 1MeTIQ (25 mg/kg, ip) administration on the duration of social interaction (a) and number of social interactions b in the SIT. The data were analyzed using two-way ANOVA and a post hoc Duncan’s MRT. The data are shown as the means ± SEM. N = 8–10 rats per group. *p < 0.05; **p < 0.01; ***p < 0.001 compared to the control (SAL) group. ^#p < 0.05; ^##p < 0.01; ^###p < 0.001 when compared to the MK-801-treated group