Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents

Summary

Ketamine, a rapid antidepressant for treatment-resistant depression, requires functional opioid receptors to produce its effects, but it does not act as an opioid itself. In rodent models, blocking opioid receptors prevented ketamine's antidepressant-like behavioral and cellular effects, while activating opioid receptors alone caused hedonic responses and failed to alleviate anhedonia. Ketamine's cellular actions were mimicked by an NMDA receptor antagonist but not by a μ-opioid agonist. The findings suggest that ketamine's antidepressant action depends on both NMDA and opioid receptor signaling, with opioid receptors playing a permissive role rather than mediating the effects directly.

Study at a glance

Abstract

Significance Ketamine, an NMDA receptor antagonist, has generated intense excitement as a therapy for treatment-resistant depression. However, ketamine and its metabolites can act on a wide range of targets, including opioid receptors, which has raised concerns. Using behavioral and cellular assays in rodents, we find that blocking opioid function prevents the antidepressant-like effects of ketamine. However, in contrast to ketamine, administration of a µ-opioid agonist is hedonic and ineffective on anhedonia/avolition. Furthermore, ketamine’s cellular actions are both mimicked and occluded by an NMDAR antagonist but not by a µ-opioid agonist. These results suggest that ketamine does not act as a μ-opioid agonist, but functional μ-opioid receptors are permissive for the antidepressant effects of ketamine. Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.