Scopolamine Exerted Antidepressant-Like Behavioral Effects via Restoring the Synaptic Plasticity in CRS-Treated Mice

摘要

Objective:Depression is a prevalent psychiatric disorder, and current first-line antidepressants are limited by their delayed onset of action and significant side effects. Although scopolamine has demonstrated rapid-acting antidepressant properties in preclinical studies, its precise mechanisms remain unclear. This study aims to systematically investigate the rapid-acting antidepressant-like behavioral effects of scopolamine and elucidate its underlying mechanisms of action. Methods: A chronic restraint stress(CRS) model was used to induce depression-like behaviors in mice. The rapid antidepressant effects of a single dose of scopolamine were assessed 24 hours post-treatment using the tail suspension test(TST) and forced swim test(FST). In vivo multichannel electrophysiological recordings were performed to monitor the spontaneous firing activity of glutamatergic pyramidal neurons in the medial prefrontal cortex(mPFC). Synaptic plasticity was evaluated by measuring plasticity-related gene expression(RT-qPCR), synaptic protein levels(immunofluorescence), and synaptic density and morphology(Golgi staining) in the mPFC and hippocampus. Results: Compared with the control group, CRS-treated mice exhibited significant depression-like behaviors, including decreased body weight and increased immobility time in the TST and FST. A single administration of scopolamine significantly reduced immobility time in both tests. Electrophysiological recordings showed that scopolamine increased the spontaneous firing rate of mPFC pyramidal neurons. Furthermore, scopolamine administration up-regulated synaptic plasticityrelated mRNA levels, increased neuronal numbers, enhanced synaptic protein expression, and elevated synaptic density. Conclusion: Scopolamine produces rapid antidepressant-like effects in CRS-treated mice, likely by enhancing synaptic plasticity in the mPFC and hippocampus. These findings provide novel insights into the mechanism of action of scopolamine and support its potential as a rapid-acting antidepressant agent.

关键词

scopolamine / antidepressant / synaptic plasticity / CRS / pyramidal neuron