Ketamine-induced static and dynamic functional connectivity changes are modulated by opioid receptors and biological sex in rats

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.