Journal of advanced research · 2026
Sigma-1 receptor activation mediates a faster antidepressant-like effect through disinhibition of the DRN5-HT-mPFCpyr neural circuit via S1R/5-HT1AR heterocomplex.
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Ren Peng, Wang Jing-Ya, Yan Jiao-Zhao, Chen Hong-Lei, Duan Jing-Yao, Xu Meng-Jie, Cui Lin-Yu, Zhang Li-Ming, Li Yun-Feng
Аннотация
BACKGROUND: The Sigma-1 receptor (S1R) represents a promising target for faster-onset antidepressants. Nevertheless, the mechanism underlying the delayed onset of therapeutic action exhibited by S1R-activating selective serotonin reuptake inhibitors (SSRIs) remains unclear. Thus, elucidating the role of S1R in mediating faster antidepressant-like effects is of considerable significance.
OBJECTIVE: This study aimed to elucidate the role of S1R in mediating faster onset antidepressant-like effects and to investigate the underlying mechanism.
METHODS: To detect the formation of S1R/5-hydroxytryptamine receptor 1A (5-HT1AR) heterocomplexes, in situ proximity ligation assay, co-immunoprecipitation, and co-localization techniques were employed. The functional role of these heterocomplexes was assessed through pharmacological interventions and behavioral tests. Furthermore, the mechanisms underlying their faster antidepressant-like effects were investigated using electrophysiological recordings and chemogenetic approaches.
RESULTS: We provide evidence for the existence of S1R/5-HT1AR heterocomplexes in the mouse brain through in-situ PLA and co-immunoprecipitation, and by co-localization assays in primary cortical neurons, and further reveal that these heterocomplexes are predominantly localized in the dorsal raphe nucleus (DRN). Pharmacological activation of S1R promoted 5‑HT1AR trafficking to the plasma membrane and enhanced functional heterocomplex formation. CREB luciferase reporter assays revealed that S1R/5‑HT1AR heterocomplexes suppress 8‑OH‑DPAT-induced inhibition of forskolin-induced CREB signaling in cells co‑expressing both receptors. Electrophysiological recordings indicated that the heterocomplex attenuated the ability of 5‑HT1AR to open G protein‑gated inwardly rectifying potassium channels, thus preventing excessive neuronal hyperpolarization and promoting neuronal activity. Disrupting S1R/5‑HT1AR complexes in DRN induced depressive‑like behaviors in mice, whereas specific activation of the DRN 5-HTergic to medial prefrontal cortex (mPFC) pyramidal (DRN5-HT-mPFCpyr) neuronal circuit alleviated these behavioral deficits.
CONCLUSION: Our findings demonstrate that S1R/5-HT1AR heterocomplex activity mediates disinhibition within the DRN5-HT-mPFCpyr neuronal circuit, underpinning the rapid antidepressant-like effects elicited by S1R activation. This highlights S1R as a promising therapeutic target for the development of faster-onset antidepressants.
OBJECTIVE: This study aimed to elucidate the role of S1R in mediating faster onset antidepressant-like effects and to investigate the underlying mechanism.
METHODS: To detect the formation of S1R/5-hydroxytryptamine receptor 1A (5-HT1AR) heterocomplexes, in situ proximity ligation assay, co-immunoprecipitation, and co-localization techniques were employed. The functional role of these heterocomplexes was assessed through pharmacological interventions and behavioral tests. Furthermore, the mechanisms underlying their faster antidepressant-like effects were investigated using electrophysiological recordings and chemogenetic approaches.
RESULTS: We provide evidence for the existence of S1R/5-HT1AR heterocomplexes in the mouse brain through in-situ PLA and co-immunoprecipitation, and by co-localization assays in primary cortical neurons, and further reveal that these heterocomplexes are predominantly localized in the dorsal raphe nucleus (DRN). Pharmacological activation of S1R promoted 5‑HT1AR trafficking to the plasma membrane and enhanced functional heterocomplex formation. CREB luciferase reporter assays revealed that S1R/5‑HT1AR heterocomplexes suppress 8‑OH‑DPAT-induced inhibition of forskolin-induced CREB signaling in cells co‑expressing both receptors. Electrophysiological recordings indicated that the heterocomplex attenuated the ability of 5‑HT1AR to open G protein‑gated inwardly rectifying potassium channels, thus preventing excessive neuronal hyperpolarization and promoting neuronal activity. Disrupting S1R/5‑HT1AR complexes in DRN induced depressive‑like behaviors in mice, whereas specific activation of the DRN 5-HTergic to medial prefrontal cortex (mPFC) pyramidal (DRN5-HT-mPFCpyr) neuronal circuit alleviated these behavioral deficits.
CONCLUSION: Our findings demonstrate that S1R/5-HT1AR heterocomplex activity mediates disinhibition within the DRN5-HT-mPFCpyr neuronal circuit, underpinning the rapid antidepressant-like effects elicited by S1R activation. This highlights S1R as a promising therapeutic target for the development of faster-onset antidepressants.