The Dorsal Raphe Nucleus: A Critical Hub in the Neurocircuitry of General Anesthesia

The dorsal raphe nucleus (DRN), the brain's primary source of serotonin, is a critical hub for regulating arousal, mood, pain, and sleep-wake cycles. Here we review what is currently known about how the DRN modulates general anesthesia. We focus on four neuronal groups, namely serotonergic, GABAergic, glutamatergic, and dopaminergic, and how they interact to shape induction and emergence. Serotonergic neurons, by promoting cortical arousal, are a key driver of anesthetic emergence; their activation accelerates recovery, while their inhibition deepens unconsciousness. GABAergic neurons provide potent local inhibition of the serotonergic system, a mechanism exploited by many anesthetic agents to induce and maintain hypnosis. Recent studies highlight functional heterogeneity within these populations, revealing that GABAergic neurons can either promote or constrain arousal depending on their projection targets, and serotonergic neurons produce opposing sleep-wake effects based on firing pattern. Glutamatergic neurons exhibit resistance to anesthetic suppression, while dopaminergic neurons encode salience and modulate pain perception. These parallel, non-serotonergic pathways expand the DRN's functional repertoire beyond its traditional serotonergic framework, and this mechanistic understanding has direct clinical implications. For patients with serotonergic disorders such as depression and anxiety, anesthetic responses often deviate from the usual pattern, so perioperative plans need to account for individual differences. Furthermore, the DRN presents a promising target for personalized anesthesia, where future strategies may leverage neuroimaging or genetic biomarkers to predict individual susceptibility and guide drug selection or novel neuromodulation therapies. Understanding the DRN at the circuit level could help translate basic neuroscience into clinical anesthetic practice and improve patient care.