The Effect of GLP-1 Agonist Liraglutide on Emotional-Cognitive Behaviors with CREB, BDNF, Trk-B Expressions in Experimental Schizophrenia-Like Behavior Model Induced by MK-801

Dönmez Kutlu M., Akıllıoğlu K.

ACTA PHYSIOLOGICA, vol.237, no.S727, pp.36, 2023 (SCI-Expanded)

  • Publication Type: Article / Article
  • Volume: 237 Issue: S727
  • Publication Date: 2023
  • Doi Number: 10.1111/apha.13909
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, MEDLINE, SportDiscus, Veterinary Science Database
  • Page Numbers: pp.36
  • Çukurova University Affiliated: Yes


AIM: Neuroprotective effects of the GLP-1agonist Liraglutide have been demonstrated in previous studies. However, there is no study in the literature for the effects of Liraglutid on MK-801-mediated NMDA receptor antagonism. In our study, the effects of Liraglutide on CREB, BDNF, Trk-B expressions and emotional-cognitive behaviors were investigated in an experimental schizophrenia-like behavior model induced by MK-801.

MATERIALS-METHODS: In our study, 8-10weeks-old-male-Balb/c mice (n=78) were injected with MK-801 (0.25 mg/kg, 0.1mL/kg body weight) and/or Liraglutide (300 mcg/kg body weight) intraperitoneally once-a-day for 7 weeks. The same volume of saline was administered to the-control-group. Mice were randomly divided into-5-groups: Saline + Saline, MK-801 + Saline, Liraglutide + Saline, MK-801 + Liraglutide-cotreatment and Liraglutide+MK-801 co-treatment. The time interval between each drug administration in all situations was 30 minutes. Following the injection emotional and cognitive behaviors were evaluated with-the-open-field-test, the-elevated-plus-maze and the Morris-water-maze-test. The hippocampus-and-prefrontal-cortex of the mice were isolated and BDNF, Trk-B, CREB-and-p-CREB expressions were evaluated by-Western-blotting. For normally distributed and parametric data, the analyses were performed by one-way ANOVA followed by Tukey’s test. For not-normally-distributed-and-parametric-data, the analyzes were performed by Kruskal-Wallis followed by Mann-Whitney-U test. Since Morris-water-maze test didn't fit the normal distribution, Friedman's-ANOVA was used followed by Wilcoxon test for comparison of group within themselves and Mann-Whitney-U test for comparison between-groups. Ethics committee approval was obtained from Çukurova University-Animal-Experiments-Local-Ethics-Committee.

RESULTS: MK-801 administration in mice caused impairment in emotional-cognitive functions. MK-801 increased the p-CREB/CREB ratio in the prefrontal cortex (p<0.001). In the MK-801+Liraglutide groups, Liraglutide could not reverse the negative effect of MK-801 on cognitive behaviors. Liraglutide administration decreased the p-CREB/CREB ratio in the prefrontal cortex and increased the BDNF/Trk-B ratio in the hippocampus (p<0.001) that increased by MK-801 administration (p<0.001). In the Liraglutide + MK-801 groups, the positive effects of Liraglutide on spatial learning and memory activity were not affected by-MK-801-administration. Liraglutide administration returned the BDNF/TrkB and p-CREB/CREB ratio in the hippocampus, the p-CREB/CREB ratio in the prefrontal cortex to the control group level.

CONCLUSION: It can be assumed that Liraglutide does not change the emotional and cognitive behaviors caused by NMDA receptor blockade, but it has a protective effect against the impairment on cognitive behaviors. In addition, it can be suggested that in the hippocampus and prefrontal cortex, GLP-1 receptors play a role in the modulation of NMDA receptor activity through CREB activation/deactivation.

Keywords: Anxiety-like behavior, BDNF, Liraglutide, MK-801, Schizophrenia, Trk-B.