N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects

Abstract

Currently available antidepressants have a delayed onset and limited efficacy, highlighting the need for new, rapid and more efficacious agents. Ketamine, an NMDA receptor antagonist, has emerged as a new rapid-acting antidepressant, effective even in treatment resistant patients. However, ketamine induces undesired psychotomimetic and dissociative side effects that limit its clinical use. The d-stereoisomer of methadone (dextromethadone; REL-1017) is a noncompetitive NMDA receptor antagonist with an apparently favorable safety and tolerability profile. The current study examined the rapid and sustained antidepressant actions of d-methadone in several behavioral paradigms, as well as on mTORC1 signaling and synaptic changes in the medial prefrontal cortex (mPFC). A single dose of d-methadone promoted rapid and sustained antidepressant responses in the novelty-suppressed feeding test (NSFT), a measure of anxiety, and in the female urine sniffing test (FUST), a measure of motivation and reward. D-methadone also produced a rapid reversal of the sucrose preference deficit, a measure of anhedonia, in rats exposed to chronic unpredictable stress. D-methadone increased phospho-p70S6 kinase, a downstream target of mTORC1 in the mPFC, and intra-mPFC infusion of the selective mTORC1 inhibitor rapamycin blocked the antidepressant actions of d-methadone in the FUST and NSFT. D-methadone administration also increased levels of the synaptic proteins, PSD95, GluA1, and Synapsin 1 and enhanced synaptic function in the mPFC. Studies in primary cortical cultures show that d-methadone also increases BDNF release, as well as phospho-p70S6 kinase. These findings indicate that d-methadone induces rapid antidepressant actions through mTORC1-mediated synaptic plasticity in the mPFC similar to ketamine.

Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants

“…Methadone is best known for treatment of opiate abuse disorder, based on the activity of l ‐methadone at opiate receptors (Gorman, Elliott, & Inturrisi, 1997). However, d ‐methadone has relatively low affinity for opiate receptor subtypes compared with l ‐methadone (Callahan, Au, Paul, Liu, & Yost, 2004), and early studies show that d ‐methadone produces antidepressant behavioral actions in the FST (Hanania, Manfredi, Inturrisi, & Vitolo, 2019) as well as several other behavioral paradigms and in the chronic unpredictable stress model (Fogaca et al, 2019). Early clinical studies have supported the possibility that d ‐methadone could be used for the treatment of depression, with fewer side effects compared to ketamine (Bernstein et al, 2019).…”

“…Recently, d-methadone, the d-isomer of methadone that acts as an NMDA receptor antagonist, was also shown to activate the mTORC1 pathway and increase BDNF release in primary cortical cultures (Fogaca et al, 2019). Methadone is best known for treatment of opiate abuse disorder, based on the activity of l-methadone at opiate receptors (Gorman, Elliott, & Inturrisi, 1997).…”

Traditional Chinese Medicine in Depression Treatment: From Molecules to Systems

“…Recent studies have demonstrated that a single dose of scopolamine (25 µg/kg) exerts rapid antidepressant actions within days in rats (Furey et al, 2010;Drevets et al, 2013). Its antidepressant actions have been revealed to be mediated through blockade of AChM1 receptor on GABA interneurons and subsequently to increase in glutamate transmission and function of spine synapse (Voleti et al, 2013;Wohleb et al, 2016;Fogaca et al, 2019).…”

REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study

“…REL-1017 (esmethadone; dextromethadone), the dextro isomer of racemic d- l -methadone, is a low affinity NMDAR channel blocker with a half maximal inhibitor concentration (IC 50 ) in the micromolar range, similarly to ketamine and dextromethorphan ( Laurel Gorman et al, 1997 ; Hanania et al, 2020 ). In preclinical studies, REL-1017 improved the depressive behavior in rodent models of depression ( Fogaça et al, 2019 ; Hanania et al, 2020 ) and increased levels of synaptic proteins in the medial prefrontal cortex ( Fogaça et al, 2019 ). Mechanistic studies indicated that the antidepressant-like effects of REL-1017 observed in rodent models were mediated by mammalian target of rapamycin complex 1 (mTORC1) and BDNF induction of neural plasticity ( Fogaça et al, 2019 ).…”