General Anesthesia Occludes Ketamine's Antidepressant Response in a Rodent Model of Chronic Stress.
Daniel Markman, Andrzej Z Wasilczuk, Joseph Michael Cichon
Psychedelic Medicine December 1, 2024 DOI: 10.1089/psymed.2024.0007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment Peer reviewed |
|---|---|
| Population | Chronically stressed adult C57/BL6 male mice |
| Interventions | Ketamine isoflurane |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressant response Chronic stress Dissociation General anesthesia Subjective effects Ketamine therapy Depression treatment Consciousness research Antidepressant mechanisms Psychedelic medicine |
| Citations | 2 |
| Key findings | Wakefulness is likely required for ketamine's rapid antidepressant responses, as coadministration of isoflurane eliminated ketamine's dissociative-like behavioral state, distinct neuronal activity patterns, and subsequent antidepressant-like effects. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 11
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science December 10, 2020
- Deep posteromedial cortical rhythm in dissociation Nature September 16, 2020
and 6 more in the library