EFFECTS OF MTOR ACTIVATORS ON BEHAVIOR IN A NOVEL ANIMAL MODEL OF TREATMENT-RESISTANT DEPRESSION

Up to 31% of patients develop treatment-resistant depression (TRD). Ketamine’s antidepressant effects in TRD are attributed to activation of the mTOR signaling pathway. However, a reliable, validated animal model of TRD is lacking. We propose a novel model to investigate behavioral effects of mTOR activators.
We developed a TRD model combining olfactory bulbectomy (OBX) and immobilization stress. OBX induced a depressive-like phenotype three weeks post-surgery, followed by two weeks of daily 4-hour immobilization in male Wistar rats (SHAM, n=20; OBX, n=12). Behavioral effects were assessed via elevated plus maze, open field, and sucrose preference tests, and cognition via Y-maze and Morris water maze. Antidepressant effects of fluoxetine (5 mg/kg) and mTOR activators ketamine (10 mg/kg) and MHY1485 (5 mg/kg) were evaluated. Three additional groups—SHAM (n=6) and OBX (n=7) without stress, and intact animals exposed only to immobilization stress —were included to evaluate each intervention individually and combined.
OBX rats exposed to immobilization stress exhibited increased anxiety, anhedonia, greater weight loss, and impaired cognitive function compared to unstressed OBX animals and SHAM controls. Neither intervention alone produced these effects. Fluoxetine had no impact, while mTOR activators improved outcomes in unstressed OBX animals. In the TRD model, only a subset responded, with behavioral deficits normalized in the responsive group.
Combining OBX and immobilization stress creates a robust TRD model. Fluoxetine was ineffective, while mTOR activators normalized behavior in responders. In future research, biochemical analyses will be performed to differentiate responders from non-responders and to elucidate the mechanisms underlying treatment resistance.