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 : official publication of the American College of Neuropsychopharmacology April 19, 2025 DOI: 10.1038/s41386-025-02108-0 via PubMed
Summary
AI-generated from the abstractKetamine, a rapid-acting treatment for depression and other neuropsychiatric disorders, works partly through the brain's opioid system, and its effects differ by sex. In rats given ketamine, blocking opioid receptors with naltrexone altered functional connectivity changes in the brain, especially in the medial prefrontal cortex (mPFC), a region of the default-mode network. These connectivity changes depended on biological sex: naltrexone affected mPFC connectivity patterns differently in males and females. Ketamine also caused a shift toward greater brain dysconnectivity and entropy, but only in male rats and only when opioid receptors were available. The findings suggest sex-specific interactions between ketamine and opioid receptors that warrant further study.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female rats |
| Interventions | Ketamine Naltrexone |
| Keywords | Neuroscience Psychopharmacology Depression treatment Sex differences Brain connectivity |
| Citations | 5 |
| Key finding | 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.