- Preclinical evidence shows selective 5-HT7 receptor antagonists produce antidepressant-like effects in forced swim, tail suspension and olfactory bulbectomy models.
- 5-HT7R primarily signals via Gαs/cAMP, with alternative Gα12 pathways; receptor is widespread and implicated in mood, circadian rhythm and cognition.
- Integration of bioengineered human-relevant platforms and CNS-targeted delivery strategies could improve mechanistic insight, translational relevance and therapeutic optimisation of 5-HT7R antagonists.
Prog Neuropsychopharmacol Biol Psychiatry. 2026 Sep 5:111915. doi: 10.1016/j.pnpbp.2026.111915. Online ahead of print.
ABSTRACT
PURPOSE OF REVIEW: Targeting serotonergic receptors, as well as the serotonin uptake, is a relevant treatment approach for the treatment of depression. The 5-hydroxytryptamine 7 receptor (5-HT7R) is a G-protein coupled receptor belonging to the serotonergic receptor family, which has received a lot of attention due to its association with mood, circadian rhythm, and cognition. This review discusses the potential of 5-HT7R antagonists to treat depression, especially focusing on the pharmacological and bioengineering approaches.
RECENT FINDINGS: The 5-HT7R is rather common in the central and peripheral tissues, such as in the brain, gastric tract, and vascular system. It primarily signals through the Gαs/cAMP pathway, although alternative Gα12-mediated signaling has also been reported. Preclinical studies show that selective 5-HT7R antagonists cause a reduction in the duration of immobility in rodent models, including the forced swim test (FST) and tail suspension test (TST), and have antidepressant-like action in the olfactory bulbectomy model of depression. Recent advances highlight the relevance of bioengineered experimental platforms and targeted drug delivery strategies to improve mechanistic understanding and optimize central nervous system (CNS)-specific modulation of 5-HT7R.
SUMMARY: Accumulating evidence supports the therapeutic relevance of 5-HT7R antagonists in depression. Transforming receptor-delivering drug-targeted therapy together with bioengineering, human-relevant experimental models, and CNS-centred delivery systems could enhance translational understanding and therapeutic optimization. Collectively, these developments make 5-HT7R antagonism a promising direction of the future antidepressant research.
PMID:42700946 | DOI:10.1016/j.pnpbp.2026.111915
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