Sex dependence of opioid-mediated responses to subanesthetic ketamine

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.

Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice

“…We also observed KET-induced hyperlocomotion in female mice, however this effect was not blocked by NAL (Fig. S1a-c), an important sex difference consistent with other reports 7,12 .…”

“…injection of low dose KET (10 mg/kg) is most sensitive to OR antagonists, consistent with similar findings with (S)-ketamine in mice 7 and racemic KET in rat 12 , and likely accounting for an early report finding no effect of naloxone on KET-induced hyperlocomotion at later timepoints 45 . Interestingly, while we and others find that male and female rodents show hyperlocomotor responses to KET 12,23 , only the male response is blocked by NAL, suggesting that the mouse model that best reflects the human physiology is quite specific, leaving open the question of how to investigate human sex-dependent responses to KET in rodent models. Finally, while (S)-ketamine appears to support a range of behaviors related to abuse liability (i.v.…”

“…Given the relatively modest effect of intra-CeA administration of an MOR antagonist, we tested a more robust behavioral paradigm, locomotor sensitization, based on recent data that ketamine and ( S )-ketamine-induced locomotor sensitization is NAL-sensitive 7,12 . We found that 20 mg/kg KET (i.p.…”

“…Rather, drug-evoked hyperlocomotion and sensitization are strongly associated with a drug’s abuse liability in rodents and humans 42 , including opioids 43 . KET-induced hyperlocomotion has been reproduced across labs for more than 40 years 7,11,16,23,44–46 , however few studies have directly tested the role of ORs in this behavior 7,12,45 .…”

“…Clinical data did not distinguish between a direct effect of ketamine at µ (MOR), δ (DOR) or κ (KOR), versus an indirect effect of naltrexone, for example by disabling endogenous opioid signaling which is known to mediate rapid antidepressant placebo responses 10 . Subsequent studies in mouse and rat testing the ketamine enantiomers have found in vitro and radiographic evidence that both (S)- and (R)-ketamine bind to MORs and KORs with an affinity marginally lower than at NMDARs, and both racemic ketamine and (S)-ketamine produced locomotor activation, locomotor sensitization, and could be self-administered in an OR-dependent fashion 7,11,12 . Preclinical studies using racemic ketamine have shown that, indeed, this interaction between ketamine and the opioid system is not consistently reflected in conventional assays used to predict antidepressant efficacy, such as the forced swim test (FST), the tail suspension test (TST) and sucrose preference test (SPT) in two stressor models of depression 13 .…”