The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions
Christopher Pittenger, Cheng Jiang, Ralph Dileone, Ronald S. Duman
Research Square October 3, 2023 preprint DOI: 10.21203/rs.3.rs-3190391/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in rats |
|---|---|
| Population | Rats |
| Interventions | Ketamine Naltrexone |
| Topics | Esketamine Ketamine |
| Key findings | Presence of β-endorphin and activation of opioid receptors in the medial prefrontal cortex are required for the antidepressant-like actions of ketamine in rats. |
Abstract
Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) were blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupted the behavioral effects of ketamine. Ketamine treatment rapidly increased levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of the gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolished both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.
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 13
- 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
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 8 more in the library