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Effects of site-selective NMDA receptor antagonists in an elevated plus-maze model of anxiety in mice.

J L Wiley, A F Cristello, R L Balster

European Journal of Pharmacology December 27, 1995 DOI: 10.1016/0014-2999(95)00506-4 (opens in new tab)

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AI-extracted from the abstract
Characteristics Animal experiment (elevated plus-maze test in mice) Peer reviewed
Population Drug-naive albino mice
Interventions Diazepam NPC 17742 N-Nitro-L-arginine methyl ester Phencyclidine ACEA 1021
Duration 5-min tests
Topics Anxiety
Key findings Diazepam and the competitive NMDA antagonist NPC 17742 increased open arm entries and open arm time in the elevated plus-maze, as did the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, though only slightly. Phencyclidine increased open arm entries but not open arm time, and ACEA 1021 affected only open arm entries at the highest dose. The authors suggest NMDA receptor antagonists show promise as anxiolytics, with differences expected among drugs acting at different sites.

Abstract

NMDA receptor antagonists have been shown to be anxiolytic in animal models of anxiety, although they have not been tested extensively. These compounds bind to several specific sites within the NMDA-receptor complex, including the NMDA site itself, the phencyclidine site, and the strychnine-insensitive glycine site. The purpose of the present study was to examine potential anxiolytic effects of site-selective NMDA receptor antagonists in the elevated plus-maze. Drug-naive albino mice were placed in the center of an elevated maze shaped like a plus sign. Two opposing arms were enclosed by high walls; the crossing arms were open. Following injection with drug or vehicle, the number of entries and time spent in each type of arm were measured during 5-min tests. Analysis of results showed that the benzodiazepine, diazepam, and the competitive NMDA receptor antagonist, NPC 17742 (2R,4R,5S 2-amino-4,5-(1,2-cyclohexyl)-7-phosphono-heptanoic acid), increased number of open arm entries and open arm time. N-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor which may interfere with the transduction of NMDA receptor activation, also increased open arm entries and time; however, the magnitude of these increases was small. The phencyclidine-site NMDA receptor antagonist, phencyclidine, increased open arm entries, but failed to significantly increase open arm time. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione), a putative glycine-site antagonist, had significant effects only on open arm entries at the highest dose tested. These results suggest that NMDA receptor antagonists show promise as potential anxiolytic agents, but that differences among antagonists acting at different cellular sites may be expected.

Comparable studies

Other preclinical and animal studies on anxiety, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats 2018 Experimental study
Chronic, Intermittent Microdoses of the Psychedelic N , N -Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents Male rats 2019 Animal study
3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Mice 2015 Preclinical experimental study
Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline Male mice exposed to chronic restraint stress 2022 Preclinical experimental study

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