The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats.

Article Details

Citation

Copy to clipboard

Hanania T, Manfredi P, Inturrisi C, Vitolo OV

The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats.

Exp Clin Psychopharmacol. 2019 Aug 1. pii: 2019-44083-001. doi: 10.1037/pha0000310.

PubMed ID

31368772 [ View in PubMed

]

Abstract

d-Methadone (dextromethadone) is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that binds to the dizocilpine (MK-801)-binding site of the receptor with an affinity comparable with that of well-established NMDAR antagonists. Considering the similar NMDAR activity of ketamine and d-methadone and the rapid and robust antidepressant effects of ketamine, we compared these 2 drugs in the forced swim test in Sprague-Dawley rats, which has been shown to be predictive of antidepressant activity for drugs with different mechanisms of action including ketamine. This study evaluated the antidepressant-like effect of d-methadone (10, 20, and 40 mg/kg) in the forced swim test 24 hr following a single-dose administration. At all doses, d-methadone significantly (p < .05) decreased immobility of rats compared with vehicle, suggesting antidepressant-like activity. In addition, the effect of d-methadone (20 and 40 mg/kg) on immobility was greater than the effect seen with ketamine (10 mg/kg). Importantly, there were no changes in locomotor activity of rats that could have confounded the immobility effects at all doses (10, 20, and 40 mg/kg) of d-methadone. This is the first demonstration that the NMDAR antagonist, d-methadone, exerts antidepressant-like activity in a preclinical animal model and that its efficacy is similar to or even stronger than that of ketamine, an antidepressant that demonstrates a rapid onset activity and robust efficacy in patients with treatment-resistant depression. d-Methadone is currently being evaluated in a Phase 2a clinical study for patients with treatment-resistant depression and could potentially represent a new effective antidepressant in the growing class of NMDAR antagonists. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Methadone	NMDA receptor (Protein Group)	Protein group	Humans	Yes	Antagonist	Details