Low doses of ketamine produce rapid antidepressant effects by activating the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway. In a rat model of depression induced by lipopolysaccharide and in PC12 nerve cells, ketamine reduced neuroinflammation, improved behavior, synaptic plasticity, and Nissl bodies. Blocking α7nAChR with methyllycaconatine or α7nAChR-siRNA reversed these effects, and the degree of reversal correlated with the dose of the blocker. A specific α7nAChR agonist, GTS-21, produced similar protective effects as ketamine, confirming the pathway's role.
Ketamine combined with docosahexaenoic acid (DHA), an unsaturated fatty acid, reversed depression-like behaviors in rats exposed to lipopolysaccharide, an inflammatory trigger. The combination reduced immobility time in forced swimming and tail suspension tests and increased sucrose preference more effectively than either agent alone. It also reversed nerve damage, reduced inflammatory cytokines IL-1, IL-6, and TNF-α in the hippocampus and PC12 cells, increased brain-derived neurotrophic factor (BDNF), inhibited PP65 nuclear translocation, and suppressed NF-κB expression while increasing P-CREB and BDNF. The findings suggest that combining ketamine with DHA may offer a more effective treatment for inflammation-driven depression by inhibiting inflammatory pathways.