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

Abstract

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.

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

“…Whether SERT and/or PMAT are involved in these actions of ketamine remains unknown. Clearly, the mechanisms contributing to ketamine’s effects are complex, given its well-known action at NMDA receptors, its myriad effects on monoamine neurotransmission, and the recently reported dependency of ketamine on the opioid system for its antidepressant properties [ 65 ]. The avenues for future research dissecting these mechanisms of action are rich.…”

Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders

“…The group further discovered that the bursting firing pattern in the habenula neurons was dependent on a change in the resting membrane potential of these neurons, which in turn was occurring due to a change in the expression levels of the channel Kir4.1 in the astrocytes that wrap these neurons [12]. Another recent study also suggests the same site of action for ketamine but attributes the effects to the function of mu-opioid receptors (MOR) and NMDA receptors (NMDAR), both of which are highly expressed in the lateral habenula [13]. Ketamine could be acting on many other neurons in the brain with NMDAR and MOR expression, but these observations together suggest a potential explanation for the rapid antidepressant effects of ketamine in comparison to alternatives like SSRIs since the site of action is upstream and can directly correct the putative monoamine imbalance linked with depressive states.…”

“…The use of animal models to dissect the underpinnings of human brain disorders is irreplaceable [76], yet studies have to fulfill a tall order of requirements where differences in cellular physiology, species differences, and the differences due to the complexity of the circuitry need to be taken into account while generating meaningful, transferable knowledge. The studies on MOR and NMDAR described above both used cLH rodents [13,64]. While this model effectively captures many aspects of a depressive state in rodents, whether it adequately represents the cellular and physiological changes associated with MDD in humans in its entirety is debatable.…”

“…This interpretation associates the clinical symptoms of depression with dysfunctional molecular and cellular changes in critical neural circuits in the brain that regulate emotion. One region of the brain that has received an unusual amount of interest in the past few years in this context is the habenula complex [10][11][12][13][14][15]. The habenula complex has been variously described as a "conductor hidden in the orchestra" [16], and as a structure at the "crossroads between basal ganglia and the limbic system", vital for decision making in vertebrates [17].…”

“…There is growing enthusiasm for the possibility that the lateral habenula is a key player in MDD based on a large number of studies in rodent models of depression [11,14,[22][23][24][25][26]. Alongside this body of research, the lateral habenula has become the anatomical target for testing antidepressants such as ketamine infusions in animals [13,14] and its action in humans [27]. Clinical studies of Deep Brain Stimulation (DBS) targeting the habenula in humans [28][29][30][31][32][33] are also underway based on favorable results in rodents [34][35][36].…”