Cortical Mechanisms Contributing to Ketamine-Induced Dissociation

Ketamine is a unique anesthetic agent that induces dissociative anesthesia, characterized by perceptual detachment, analgesia, and altered states of consciousness. Beyond its widespread use in anesthesia, subhypnotic ketamine dosing has emerged as a rapid-acting antidepressant and a valuable model for probing the neural mechanisms underlying consciousness and neuropsychiatric disorders. At the core of its effects are actions on cortical circuits, primarily through NMDA receptor and HCN1 channel antagonism, disinhibition of pyramidal neurons, and altered thalamocortical connectivity. This review brings together emerging findings from ketamine pharmacology, cell type-resolved and region-specific in vivo imaging, and systems neuroscience to define how ketamine alters cortical circuit dynamics to drive dissociation. We further explore the intriguing possibility that ketamine freely diffuses into and concentrates within intracellular compartments and, in doing so, modulates neuronal excitability, intracellular signaling, and an epigenetic state, even following a single dose. A deeper mechanistic understanding of these cortical and cellular processes will not only advance our knowledge of ketamine's complex pharmacology but may also inform new therapeutic strategies for treatment-resistant depression and facilitate the study of diverse states of consciousness.