TREK-1 Mediates The Alleviative Effects of GABAB Receptor Antagonism on Depression-Like Behavior in Chronic Unpredictable Stress Rats

Abstract GABAB receptor (GABAB R) antagonists are known to have antidepressant effects. TWIK-related potassium channel-1 (TREK-1) plays a role in GABAB R signaling. However, the role of TREK-1 in the antidepressant actions of GABAB R antagonist is still unclear. This study aimed to investigate whether TREK-1 mediates the antidepressant actions of GABAB R antagonist. To investigate this hypothesis, chronic unpredictable stress rats were treated with a GABAB R antagonist, GABAB R agonist, or TREK-1 blocker. Depression-like behavior was assessed by open field tests and sucrose preference tests. GABAB R and TREK-1 protein levels were measured by western blotting. The results demonstrated that the GABAB R antagonist alleviated depression-like behavior and reversed the decrease in hippocampal TREK-1 protein expression that characterizes chronic unpredictable stress rats. Conversely, the GABAB R agonist exacerbated depression-like behavior and further decreased hippocampal TREK-1 protein expression. In addition, the TREK-1 blocker alleviated the depression-like behavior of chronic unpredictable stress rats and increased hippocampal TREK-1 protein expression. These results suggest that the alleviative effects of the GABAB receptor antagonist on depression-like behavior in chronic unpredictable stress rats are at least partially mediated through TREK-1. These novel findings will be helpful for the clinical therapy of depression.