Ketamine-induced static and dynamic functional connectivity changes are modulated by opioid receptors and biological sex in rats.
Valeria Grasso, Joseph Tennyson, Raag D. Airan, Tommaso Di Ianni
Neuropsychopharmacology April 19, 2025 DOI: 10.1038/s41386-025-02108-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female rats |
| Interventions | Ketamine Naltrexone |
| Topics | Esketamine Ketamine |
| Keywords | Psychopharmacology Depression treatment Sex differences Brain connectivity |
| Citations | 5 |
| Key findings | Ketamine-induced functional connectivity changes are modulated by opioid receptor blockade in a sex-dependent manner, with opioid-dependent shifts toward dysconnectivity and increased brain entropy occurring only in male rats. |
Abstract
Subanesthetic ketamine is currently used as a rapid-acting treatment for varied neuropsychiatric disorders. However, the mechanistic underpinnings of its therapeutic action remain unclear, and emerging clinical and preclinical evidence highlights a potential involvement of the opioid system. We used pharmacological functional ultrasound imaging data acquired during and after ketamine administration in male and female rats pretreated with naltrexone, an opioid receptor antagonist, or vehicle. We found that ketamine-induced functional connectivity changes are modulated by opioid receptor blockade, and that these responses are dependent on biological sex. Specifically, naltrexone sex-dependently altered the connectivity patterns within the medial prefrontal cortex (mPFC), a key node of the brain's default-mode network, and between the mPFC and other functional nodes. Furthermore, ketamine produced an opioid-dependent shift toward states of increased dysconnectivity and brain entropy in male rats only. Our findings warrant further investigation into the neurophysiological underpinnings of ketamine action and potential sex-specific interactions with opioid receptors.
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 3
- Mu Opioid Receptor Activation is Required for NMDA Receptor Antagonist Effects on Stress-induced Maladaptive Behavior. Biological Psychiatry July 7, 2025
- From psychache to neuroplasticity: A unified rescue-repair model of Ketamine's anti-suicidal action. Neuroscience & Biobehavioral Reviews June 7, 2026
- Network pharmacology of cellular targets in major depressive disorder and differential mechanisms of fluoxetine, ketamine and esketamine Computational and Structural Biotechnology Journal December 29, 2025
Cites 30
- A default mode of brain function Proceedings of the National Academy of Sciences January 16, 2001
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Meditation experience is associated with differences in default mode network activity and connectivity Proceedings of the National Academy of Sciences November 23, 2011
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
and 25 more in the library