4-F-PCP, a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism
Darlene Mae Ortiz, Mikyung Kim, Hyun Jun Lee, Chrislean Jun Botanas, Raly James Perez Custodio, Leandro Val Sayson, Nicole Bon Campomayor, Chaeyeon Lee, Yong Sup Lee, Jae Hoon Cheong, Hee Jin Kim
Biomolecules & Therapeutics February 15, 2023 Peer reviewed DOI: 10.4062/biomolther.2022.159 via OpenAlex
Summary
4-F-PCP, a novel NMDA receptor antagonist similar to ketamine, demonstrated antidepressant-like effects in mice at doses of 3 and 10 mg/kg. These effects were maintained with repeated treatments and were associated with increased expression of proteins linked to depression and synaptic plasticity. Importantly, 4-F-PCP at the 3 mg/kg dose did not negatively impact cognitive function over a long-term treatment period of up to 21 days. This suggests potential for future antidepressant development.
Study at a glance
| Population | mice |
|---|---|
| Key finding | 4-F-PCP at doses of 3 and 10 mg/kg showed antidepressant-like effects and did not alter cognitive function in mice. |
Abstract
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 antagonist, 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 effects. 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.