Role of hypothalamic magnocellular neurons in mediating the psychedelic and antidepressant properties of ketamine

Abstract

The search for effective, short-acting, and reversible anesthetics has led to the creation of ketamine, widely used in veterinary medicine but with limited clinical application in humans due to its hallucinogenic and dissociative effects, which have popularized it as a recreational drug. Recently, its use in treating treatment-resistant depression has gained attention, demonstrating antidepressant effects in clinical studies and resulting in the FDA approval of S-ketamine intranasal spray in 2019 for adults with refractory depression. However, there remains a lack of consensus on the molecular and cellular mechanisms underlying the anesthetic, psychedelic, and antidepressant actions of ketamine, as well as on the specific regions of the central nervous system and types of neurons involved in its effects on consciousness and mood. Recently, a study demonstrated that several general anesthetics, including ketamine, suppress neuronal activity in the central nervous system, except for a group of neurons in the hypothalamus consistently activated by these anesthetics. These neurons, known as hypothalamic magnocellular neurons (MCNs), are located in the supraoptic nucleus (SON) and are responsible for synthesizing vasopressin (AVP) and prodynorphin (PDYN), predominantly. Activation of these neurons using excitatory DREADDs intensified the effects of general anesthetics, while inactivation via inhibitory DREADDs reduced the duration of anesthesia. Furthermore, studies indicate that general anesthetics not only activate MCNs in the SON but also neurons in the paraventricular nuclei of the hypothalamus (PVN), where MCNs producing AVP and oxytocin (OXT) are located. These results suggest that these AVP and OXT-producing neurons play an essential role in regulating anesthesia and sleep. Interestingly, not only do parvocellular neurons of the PVN project to various regions of the CNS, but also MCNs of the PVN and SON send axonal projections to brain nuclei that regulate pain perception, affective/emotional states, social behavior, and fear. This evidence seems to align with the involvement of AVP and OXT in regulating emotional and behavioral responses, as well as processing social information. Dysfunctions in these processes are associated with the development of various mental disorders and potentially contribute to the psychedelic and antidepressant properties of ketamine, which have not been fully understood yet. To date, the effects of administering psychedelic or antidepressant doses of ketamine on the activity of these neurons have not been explored, nor has the role of their neuropeptides and receptors as mediators of psychedelic or antidepressant effects. Additionally, the potential effects on metabolic parameters associated with the behavioral effects of moderate and low doses of ketamine have not yet been investigated, offering possible relevant evidence of the systemic neuroendocrine repercussions induced by the drug. Another crucial point is the influence of sex on behavioral responses to subanesthetic doses of ketamine, along with its association with the activity patterns of MCNs. The evident sexual dimorphism in electrophysiological patterns, gene expression, and the composition and distribution of MCNs are particularly relevant when considering epidemiological data indicating significant sex differences in the incidence of drug use disorders and depression. Therefore, we propose to investigate how subanesthetic doses of ketamine affect the activity of MCNs and study the role of these neurons in inducing its psychedelic and antidepressant effects, thus contributing to advancing the understanding of ketamine action and the role of MCNs in neuropsychiatric disorders and drug abuse. (AU)