General Anesthesia Occludes Ketamine's Antidepressant Response in a Rodent Model of Chronic Stress

Psychedelic-induced experiences are thought to play an important role in the therapeutic actions of rapid-acting antidepressants. General anesthesia is one scenario in which patients can be rendered unconscious and masked to the psychedelic treatment, providing a simple yet effective method to examine drug-induced changes in the brain devoid of experiences.

Chronically stressed adult C57/BL6 male mice were given subhypnotic ketamine alone or ketamine and GABAergic anesthetic isoflurane at sedative (0.6%) and general anesthetic levels (1.2%). Behavioral testing and in vivo two-photon neuronal calcium responses were recorded at the time of drug administration. Antidepressant-like responses were recorded 24 h later.

We find that both ketamine's dissociative-like behavioral state and distinct patterns of neuronal activity in pyramidal neurons of prefrontal cortex during administration are eliminated by the coadministration isoflurane at both doses. Following coexposure, both ketamine's antidepressant-like behavioral response and neuronal induction of activity-dependent molecular plasticity marker c-Fos fail to manifest.

These findings provide behavioral and neurophysiological evidence that wakefulness is likely required for ketamine's rapid antidepressant responses. Thus, altering the level of consciousness to suppress psychedelic-induced experiences might impair activity-dependent plasticity mechanisms that confound the study of psychedelic-induced therapeutic effects.