Revolutionary Discovery: Fast-Acting Antidepressant Target with Minimal Side Effects Unveiled by Scientists

The worldwide impact of anxiety- and depression-linked disorders is increasing. While numerous medications have been formulated to tackle these issues, present treatments come with various limitations, such as delayed efficacy and negative side effects from long-term use. This highlights the pressing requirement for new, quickly-acting therapeutic options that cause minimal side effects.

The delta opioid receptor (DOP) is instrumental in regulating mood, making it an appealing target for therapeutic strategies. Research has demonstrated that selective DOP agonists (substances that activate DOP), including SNC80 and KNT-127, exhibit antidepressant and anxiolytic (anti-anxiety) actions in animal models. Nevertheless, the exact molecular mechanisms that drive their effects are still not fully understood. Grasping the neurological processes that govern mood regulation and DOP action is essential for promoting DOP agonists as therapeutic solutions.

In pursuit of this, Professor Akiyoshi Saitoh and Mr. Toshinori Yoshioka from Tokyo University of Science (TUS), Japan, performed a series of experiments to clarify the cellular and molecular processes that contribute to the antidepressant-like effects of KNT-127. Further elucidating their research published online on December 6, 2024, in Molecular Psychiatry, Prof. Saitoh states, “Integrating the findings of this study with our past research, we believe that DOP agonists possess an unprecedented mechanism of action and have the potential to transform depression treatment with superior efficacy and safety compared to current medications.”

In their earlier research, the scientists carried out the forced swimming test (FST), which is recognized to provoke depression-like helplessness in untreated mice, to ascertain whether KNT-127 might produce antidepressant-like results. They compared the reactions of animals treated with KNT-127 against control groups. Remarkably, a single administration of KNT-127, 30 minutes before the test, markedly decreased immobility counts, indicating an antidepressant-like effect facilitated by DOP stimulation.

The mechanistic (or mammalian) target of rapamycin (mTOR) signaling pathway, linked to rapid antidepressant effects, was examined for its role in KNT-127’s mechanisms. The researchers administered rapamycin—a mTOR inhibitor—prior to KNT-127 treatment to the mice. Indeed, rapamycin counteracted the decrease in immobility counts caused by KNT-127 in the FST, suggesting that the antidepressant-like effects of KNT-127 were mediated through mTOR signaling.

Subsequently, the team evaluated the activation of mTOR signaling-related proteins in brain areas associated with mood disorders and charted specific phosphorylation patterns in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. The results indicated that the antidepressant-like effects were chiefly mediated by Akt signaling in the mPFC, while the anxiolytic effects correlated with amygdala activation through ERK signaling.

Further experiments in a depression mouse model indicated that direct injection of KNT-127 into the medial prefrontal infralimbic cortex region (IL-PFC) resulted in an antidepressant effect via the PI3K and mTOR pathways. The IL-PFC in rodents is thought to be functionally analogous to Brodmann Area 25 in humans, which is associated with mood control. Additionally, the antidepressant-like effects of KNT-127 were found to be independent of the strain, gender, or age of the subjects, and another DOP agonist, SNC80, also demonstrated similar effects, emphasizing the extensive therapeutic potential of DOP agonists.

Moreover, the application of KNT-127 to isolated IL-PFC brain tissue enhanced glutamatergic transmission by suppressing the release of gamma-aminobutyric acid (GABA—a crucial neurotransmitter), bolstering the direct effect of DOPs on the IL-PFC. The study revealed that most DOPs were expressed in parvalbumin-positive interneurons found in the IL-PFC, providing new insights into the cell-specific expression of DOP across various brain regions and augmenting our comprehension of its mechanisms.

Prof. Saitoh wraps up by discussing the clinical significance of their findings, stating, “Our research offers a proof of concept for the antidepressant effect of DOP and could significantly enhance the clinical development of DOP agonists as therapeutic solutions. Furthermore, the IL-PFC is a region implicated in resistance to traditional antidepressant treatment. Thus, DOP agonists may prove to be more efficacious in patients who are unresponsive to existing therapies.”

We are hopeful that these discoveries will lead to an effective intervention for individuals struggling with depression.