Cordycepin Produces A Rapid And Robust Antidepressant Effect Via Enhancing Prefrontal AMPAReceptor Signaling Pathway

Background:The development of rapid and safe antidepressant for the treatment of major depression is in urgent demand. Converging evidence suggests that glutamatergic signaling seems to play important roles in the pathophysiology of depression.Methods:We studied the antidepressant effect of Cordycepin(3’-deoxyadenosine, 3’-dA) and the critical role of AMPA receptor in male CD-I mice via behavioral and biochemical experiments. After Cordycepin treatment, the phosphorylation and synaptic localization of AMPA receptor GluRl and GluR2 were determined in the prefrontal cortex (PFC) and hippocampus (HIP). The traditional antidepressant imipramine was applied as positive control.Results:We found that an injection of Cordycepin led to a rapid and robust antidepressant effect after 45 minutes in tail suspension and forced swim tests, significantly faster and stronger than imipramine. This antidepressant effect remained after 5 days treatment with Cordycepin. Unlike the psycho-stimulants, Cordycepin did not show a hyperactive effect in open field test. After 45 minutes or 5 days treatment, Cordycepin enhanced GluR1 S845 phosphorylation in both PFC and HIP. In addition, after 45 minutes treatment, Cordycepin significantly up-regulated GluRl S845 phosphorylation and GluRl, but not GluR2 levels at the synapses in the PFC. After 5 days treatment, Cordycepin significantly enhanced GluRl S845 phosphorylation and GluRl, but not GluR2 at the synapses in the PFC and HIP. Moreover, AMPA specific antagonist GYKI 52466 was able to block the rapid antidepressant effect of Cordycepin.Conclusion:This study identified Cordycepin as a novel rapid antidepressant with clinical potential and multiple beneficial mechanism(s), particularly regulating prefrontal AMPA receptor signaling pathway.