Depression stands as one of the most prevalent mental health disorders globally, yet existing antidepressants have not fully met the diverse needs of many patients. Recently, neuroscientists at the City University of Hong Kong (CityU) have uncovered a small molecule that demonstrates efficacy in alleviating stress-induced depressive symptoms in mice by impeding the formation of aversive memories at a lower dosage. This discovery opens up a novel avenue for the prospective development of antidepressants.

Professor He Jufang, the Wong Chun Hong Chair Professor in Translational Neuroscience at CityU, emphasized the pressing need for more effective depression treatments, pointing out the limitations of conventional methods such as drug therapy with delayed onset and psychotherapy.

Earlier research had highlighted the connection between stress-induced changes in neural plasticity, particularly in the brain’s valence-coding systems, and mental health conditions like depression, post-traumatic stress disorders, and anxiety disorders. Depression was also associated with hyperactivation of the amygdala, although the underlying neural mechanisms remained unclear.

Professor He’s research group, specializing in memory formation and encoding, had previously identified cholecystokinin (CCK) as a key neuromodulator crucial for inducing long-term potentiation (LTP) – a sustained enhancement in neuronal communication fostering memory formation. Their investigation extended to the role of CCK and CCK-B receptors in mediating neuroplasticity and various forms of memory formation.

Building on these findings, the researchers hypothesized that CCK might facilitate aversive memory formation in the basolateral amygdala (BLA), contributing to the development of depression. In their latest study, they tested this hypothesis using diverse experimental methods and found that a CCK-B receptor antagonist called YM022 demonstrated an antidepressant-like effect by blocking neuroplasticity-induced aversive memory formation in mice.

Results from in-vitro recordings in the BLA showed a significant suppression of neuroplasticity with YM022. Behavioral tests further confirmed the antagonist’s efficacy, revealing reduced depressive behaviors in mice treated with the CCK-B receptor antagonist. Notably, YM022 exhibited anxiolytic effects at an extremely low dose (3.0 ug/kg), 3,000 times lower than the required dosage of current antidepressants.

Professor He highlighted these results as indicative of CCK-B receptors being a potential target for depression treatment, with YM022 emerging as a promising antidepressant candidate due to its remarkably small effective dose. The focus now shifts to understanding the precise mechanisms and potential side effects of CCK-B receptor antagonists, setting the stage for future clinical trials involving human subjects.


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