Sex dependence of opioid-mediated responses to subanesthetic ketamine
bioRxiv Preprint Server – September 06, 2022
Source: bioRxiv
Summary
A surprising finding reveals how a rapid-acting antidepressant works differently in males and females. Research into ketamine's ability to quickly reduce depression symptoms found its beneficial brain effects, linked to mood and reward, depend on opioid signaling in males. This crucial opioid connection was absent in females and reversed in males without male hormones. This suggests ketamine's positive impact on depression is strongly influenced by sex, via opioid pathways in the brain.
Abstract
Subanesthetic ketamine rapidly and robustly reduces depressive symptoms in patients with treatment-resistant depression. While it is commonly classified as an N-methyl D-aspartate receptor (NMDAR) antagonist, our picture of ketamine’s mechanistic underpinnings is incomplete. Recent clinical evidence has indicated, controversially, that a component of the efficacy of ketamine in depression may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that blocking opioid receptors suppressed neurophysiologic changes evoked by ketamine, but not by a more selective NMDAR antagonist, in regions implicated in the pathophysiology of depression and in reward processing. Importantly, this opioid-dependent response was strongly sex dependent, as it was not evident in female subjects and was fully reversed by surgical removal of the male gonads. We observed similar opioid-mediated sex-dependent effects in ketamine-evoked structural plasticity and behavioral sensitization. Together, these results underscore the potential for ketamine to induce its affective responses via opioid signaling, and indicate that this opioid dependence may be strongly influenced by subject sex. These factors should be more directly assessed in future clinical trials.