Low-Dose Ketamine Improves LPS-Induced Depression-like Behavior in Rats by Activating Cholinergic Anti-inflammatory Pathways

About 16% of the world's population has major depressive disorder. Traditional antidepressants have slow effect rates and low response rates. Many studies have shown that low doses of ketamine can produce rapid and effective antidepressant effects. However, its mechanism of action needs further exploration. Lipopolysaccharide (LPS) was used to establish a depression model in rats and PC12 nerve cells were used for in vitro experiments. (2,4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a specific agonist of α7 nicotinic acetylcholine receptors (α7 nAChRs), was used to compare the rapid antidepressant effect of ketamine. Different doses of α7 nAChR antagonist methyllycaconatine (MLA) and α7 nAChR-siRNA were used to interfere with the protective effects of ketamine on neuroinflammation in rats and PC12 cells, respectively. MLA intervention downregulated the anti-inflammatory effects of ketamine and decreased the effects of ketamine on behavior, synaptic plasticity, and Nissl bodies in the neuronal cells. Moreover, the dose of MLA was positively correlated with the inhibitory effect in rat hippocampi and the protective effects of GTS-21 were consistent with ketamine. These results demonstrated that low-dose ketamine could produce neuroprotective effects by activating the α7 nAChR-mediated cholinergic anti-inflammatory pathway (CAP) in depression, resulting in a rapid antidepressant effect.