Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Matthew E. Klein, Joshua Chandra, Salma A. Sheriff, R. Malinow
Proceedings of the National Academy of Sciences January 15, 2020 DOI: 10.1073/pnas.1916570117 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rodents (rats and unspecified rodents) |
| Interventions | ketamine opioid antagonist μ-opioid agonist NMDA receptor antagonist |
| Topics | Esketamine Ketamine |
| Citations | 157 |
| Key findings | Ketamine's antidepressant-like effects require functional μ-opioid receptors, but ketamine does not act as a μ-opioid agonist. |
Abstract
Significance Ketamine, an NMDA receptor antagonist, has generated intense excitement as a therapy for treatment-resistant depression. However, ketamine and its metabolites can act on a wide range of targets, including opioid receptors, which has raised concerns. Using behavioral and cellular assays in rodents, we find that blocking opioid function prevents the antidepressant-like effects of ketamine. However, in contrast to ketamine, administration of a µ-opioid agonist is hedonic and ineffective on anhedonia/avolition. Furthermore, ketamine’s cellular actions are both mimicked and occluded by an NMDAR antagonist but not by a µ-opioid agonist. These results suggest that ketamine does not act as a μ-opioid agonist, but functional μ-opioid receptors are permissive for the antidepressant effects of ketamine. Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.
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
Cited by 85
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology, Biochemistry, and Behavior February 5, 2020
and 80 more in the library
Cites 7
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review Therapeutic Advances in Chronic Disease April 13, 2015
- The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One June 14, 2016
- Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder JAMA Psychiatry March 1, 2019
and 2 more in the library