Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.
Keywords: angiotensin 2 type 2 receptor (AT2R); compound 21; fear conditioning; neurotrophin receptor type 2 (NTRK2); renin-angiotensin system (RAS).