The effect of GLP-1 agonist Liraglutide on BDNF and Trk-B expressions and emotional-cognitive behaviors in an experimental schizophrenia-like behavior model induced by MK-801

Although the neuroprotective effects of GLP-1 agonist Liraglutide are known, its effect on MK-801-mediated NMDA receptor antagonism have not been demonstrated in the literature. In our presented 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. For that purpose, 8-10 weeks old male Balb/c mice (n=78) were injected with MK-801 (0.25 mg/kg, 0.1 mL/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 cotreatment. 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 that were not included in the behavioral experiments from each group were isolated and BDNF, Trk-B, CREB and p-CREB expressions were evaluated by Western blotting. In our study, MK-801 administration in mice caused impairment in emotional and 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. In 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.