Rislenemdaz treatment in the lateral habenula improves despair-like behavior in mice

The specific GluN2B antagonist rislenemdaz (Ris; a.k.a. MK-0657 and CERC-301) is in phase II clinical trial as an antidepressive drug, but the working mechanism for its antidepressant effects is not clearly understood. Given the important role of the lateral habenula (LHb) in the pathogenesis of depression and the fact that GluN2B-containing N-methyl-D-aspartate receptors and brain-derived neurotrophic factor (BDNF) are expressed in the LHb, we conducted a study to examine whether the LHb mediates Ris’ antidepressant effects in a chronic restraint stress (CRS)-induced depressive-like mouse model. In this study, Ris was administered systemically or locally into the LHb. Short hairpin RNAs were used to knockdown BDNF in the LHb. Depressive-like behaviors were assessed with the open field test, forced swimming test, tail suspension test, and sucrose preference test. Expression of GluN2B, BDNF, and c-Fos in the LHb were analyzed with western blotting and immunohistochemistry under condition with Ris administered systemically or with BDNF knockdown in the LHb. We found that both systemic and intra-LHb administration of Ris alleviated CRS-induced despair-like behavior and that systemic Ris reduced LHb expression of GluN2B, BDNF, and c-Fos (a neuronal activity marker). Specific knockdown of BDNF in the LHb prevented CRS-induced despair-like behavior, while preventing CRS-induced increases in BDNF and c-Fos expression in the LHb. Together these results suggest that Ris may exert its antidepressant effects through affecting the LHb such as downregulating BDNF expression in the LHb.