Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression

We previously revealed that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor and mammalian target of rapamycin signaling contributed to the antidepressant-like effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists, suggesting that the signaling pathway may be similar to the molecular mechanisms underlying the antidepressant-like action of ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exertes rapid and sustained antidepressant effects in patients with depressive disorder. Although brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling reportedly participates in the antidepressant-like effects of ketamine, the involvement of BDNF/TrkB signaling in the action of mGlu2/3 receptor antagonists has not been investigated. We therefore examined whether the activation of BDNF/TrkB signaling is required for the antidepressant-like effects of LY341495, an mGlu2/3 receptor antagonist, in animal models of depression such as the tail suspension test (TST) and the novelty-suppressed feeding test (NSFT). The administration of LY341495 at 30 min prior to the test exerted antidepressant-like effects (acute effects) lasting for at least 24 h (sustained effects) when evaluated using the TST and NSFT. Pretreatment with K252a, a TrkB tyrosine kinase inhibitor, blocked the sustained, but not the acute, effects of LY341495. These results suggest that BDNF/TrkB signaling may be involved in the sustained antidepressant-like effects of LY341495, as observed for ketamine treatment.

► LY341495 exerted antidepressant-like effects in the tail suspension test.
► LY341495 exerted antidepressant-like effects in the novelty-suppressed feeding test.
► Antidepressant-like effects of LY341495 were sustained for 24 h.
► K252a blocked the sustained, but not acute, antidepressant effects of LY341495.