Targeting Anhedonia and Social Deficits in Schizophrenia: The Therapeutic Potential of TAK-041

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.