This study investigates the sex-dependent effects of opioid receptors on the neural and behavioral responses to subanesthetic ketamine in rats. Using functional ultrasound imaging (fUSI), the researchers found that blocking opioid receptors suppressed neurophysiological changes induced by ketamine in male rats but not in female rats. These effects were region-specific, particularly in the prefrontal cortex, nucleus accumbens, and lateral habenula, and were gated by male sex hormones. The opioid-mediated responses were also reflected in changes in postsynaptic density protein expression and locomotor sensitization, which were blocked by opioid receptor blockade in male rats but not in females. Additionally, chronic naltrexone treatment upregulated mu opioid receptors in female rats, potentially explaining the lack of behavioral adaptations observed in this sex. The findings suggest that the opioid-dependent effects of ketamine are sex-dependent and highlight the importance of considering sex as a biological variable in clinical trials of ketamine's therapeutic and adverse effects.This study investigates the sex-dependent effects of opioid receptors on the neural and behavioral responses to subanesthetic ketamine in rats. Using functional ultrasound imaging (fUSI), the researchers found that blocking opioid receptors suppressed neurophysiological changes induced by ketamine in male rats but not in female rats. These effects were region-specific, particularly in the prefrontal cortex, nucleus accumbens, and lateral habenula, and were gated by male sex hormones. The opioid-mediated responses were also reflected in changes in postsynaptic density protein expression and locomotor sensitization, which were blocked by opioid receptor blockade in male rats but not in females. Additionally, chronic naltrexone treatment upregulated mu opioid receptors in female rats, potentially explaining the lack of behavioral adaptations observed in this sex. The findings suggest that the opioid-dependent effects of ketamine are sex-dependent and highlight the importance of considering sex as a biological variable in clinical trials of ketamine's therapeutic and adverse effects.