Ketamine, 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.
Ketamine rapidly reduces depressive symptoms in treatment-resistant depression, but its mechanisms are not fully understood. Recent clinical evidence controversially suggests that ketamine's efficacy may depend on opioid signaling. In rats, blocking opioid receptors suppressed ketamine-induced neurophysiologic changes in brain regions linked to depression and reward, but did not affect changes from a more selective NMDA receptor antagonist. This opioid-dependent response was strongly sex-dependent: absent in females and reversed by removing male gonads. Similar sex-dependent opioid effects appeared in ketamine-evoked structural plasticity and behavioral sensitization. These results indicate that ketamine may induce affective responses via opioid signaling, with subject sex as a strong influence, warranting direct assessment in future clinical trials.