Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray

Rationale Clinical reports reveal that scopolamine, an acetylcholine muscarinic receptor antagonist, exerts rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic effects have not been fully identified. Objectives The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG). Methods We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG. Results The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects. Conclusions Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.

Automated summary

This study explored the mechanisms underlying the antidepressant-like effects of scopolamine through its action in the vlPAG. Results demonstrated that scopolamine exerted antidepressant effects in a mouse model of depression induced by chronic restraint stress (CRS), and reversed the inhibition of glutamatergic transmission in the vlPAG caused by CRS. Additionally, the study found that the antidepressant effects of scopolamine depended on the activation of L-type voltage-dependent calcium channels (VDCC), resulting in the release of brain-derived neurotrophic factor (BDNF) and the engagement of the TrkB receptor and downstream mTORC1 signaling in the vlPAG.