Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Ji, R.; Zhao, Y.; Huang, Z.; Li, X.; Chen, Y.; Gan, Y.; Zhang, T.; Hai, A.; Lai, S.; Liu, T.; Yin, Y.; Sun, Y.; Yuan, Y.; Xu, B.; Liu, J.; Ke, B.

doi:10.64898/2026.02.17.706054

bioRxiv · 10.64898/2026.02.17.706054

Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Ji, R.·Zhao, Y.·Huang, Z.·Li, X.·Chen, Y.·Gan, Y.·Zhang, T.·Hai, A.·Lai, S.·Liu, T.·Yin, Y.·Sun, Y.·Yuan, Y.·Xu, B.·Liu, J.·Ke, B.

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Abstract

Pharmacological control of emergence from general anesthesia remains strikingly limited. Clinically available antagonists are largely drug-class specific, leaving recovery dependent on anesthetic clearance rather than to an actively programmable switch in brain state. Through phenotypic screening of a structurally diverse natural-product library, we identified BN3 (L-(-)-camphor) as a broad-spectrum emergence agent. BN3 robustly shortened recovery from propofol anesthesia across species--from mice and rats to rabbits, dogs, and rhesus monkeys--and remained effective after continuous infusion. In rodents, BN3 also accelerated emergence from mechanistically distinct anesthetics, including etomidate, remimazolam, sodium {gamma} - hydroxybutyrate, midazolam, ketamine, sodium pentobarbital, and isoflurane. EEG recordings revealed a rapid cortical shift from slow-wave dominance to a wake-like high-frequency spectrum. Mechanistically, BN3 preferentially recruited ventral tegmental area (VTA) glutamatergic neurons: chemogenetic silencing abolished the BN3-evoked EEG spectral shift and strongly attenuated behavioral acceleration of emergence, whereas optogenetic activation of these neurons was sufficient to promote recovery. BN3 increased glutamate release in the nucleus accumbens and medial prefrontal cortex, and projection-specific inhibition of VTA[->]NAc or VTA[->]mPFC outputs blunted BN3-induced emergence. These findings define a VTA-centered glutamatergic arousal circuit that can be pharmacologically recruited as a common gateway for anesthetic-independent emergence.

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Ji, R., Zhao, Y., Huang, Z., Li, X., Chen, Y., Gan, Y., Zhang, T., Hai, A., Lai, S., Liu, T., Yin, Y., Sun, Y., Yuan, Y., Xu, B., Liu, J., Ke, B.. 2026-02-18. Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia. https://doi.org/10.64898/2026.02.17.706054

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