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

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2019-12, Vol.44 (13), p.2230-2238
• Main Authors: Fogaça, Manoela V, Fukumoto, Kenichi, Franklin, Tina, Liu, Rong-Jian, Duman, Catharine H, Vitolo, Ottavio V, Duman, Ronald S
• Format: Article
• Language: English
• Subjects: Animals; Antidepressants; Antidepressive Agents - administration & dosage; Anxiety; Behavioral plasticity; Brain-derived neurotrophic factor; Dendritic Spines - drug effects; Dendritic Spines - physiology; Excitatory Postsynaptic Potentials - drug effects; Glutamic acid receptors (ionotropic); Hedonic response; Ketamine; Ketamine - administration & dosage; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Methadone; Methadone - administration & dosage; Motivation; N-Methyl-D-aspartic acid receptors; Postsynaptic density proteins; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rapamycin; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Reinforcement; Ribosomal protein S6 kinase; Signal Transduction - drug effects; Stereoisomers; Sucrose; Sugar; Synapsin; Synaptic plasticity; Urine
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-019-0501-x

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.