4-F-PCP, a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism

Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4-F-PCP analog is a novel PCP analog that is also an NMDA receptor antago-nist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its ef-fects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.