The abstract discusses the challenges of treating negative symptoms in
schizophrenia (SCZ) and the role of the brain's frontocortico-temporal circuits and cortico-striatal loops. It highlights the significance of the habenula, a region associated with reward and motivation, which is affected in SCZ patients and linked to deficits in feedback processing. The
orphan GPCR,
GPR139, is noted for its expression in the CNS and its potential in modulating negative symptoms through its influence on the habenula circuitry.
A study involving an unpredictable chronic mild stress (uCMS) protocol, which simulates
depression, was conducted on animals. The three-chamber social interaction test was utilized to evaluate social behavior, and the activation of habenula neurons was measured using c-fos expression. Additionally, dopamine release in the nucleus accumbens (NAc) was examined through microdialysis.
The research found that the GPR139 agonist
TAK-041 increased cFOS expression in the habenula of wild-type mice, but not in mice lacking GPR139. Chronic dosing of TAK-041 did not lead to desensitization of cFOS in the habenula. The agonist reduced dopamine release induced by
amphetamine and
nicotine in the NAc. Moreover, TAK-041 was effective in reversing anhedonia and anxiety-related behaviors caused by uCMS, and it normalized disrupted circadian regulation of corticosterone secretion. It also mitigated the effects of uCMS on the morphology of neurons in the hippocampus and NAc.
The study concludes that TAK-041, by modulating the habenula circuitry, may be beneficial for treating
anhedonia and possibly depression. Furthermore, it suggests that TAK-041 could improve social interaction deficits observed in various rodent models related to SCZ negative symptoms. The author was affiliated with Takeda during the study.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
