Biological Psychiatry Published: May 09, 2021DOI:

Fluoroethylnormemantine, a Novel NMDA Receptor Antagonist, for the Prevention and Treatment of Stress-Induced Maladaptive Behavior. Briana K.Chen, Victor M.Luna, Margaret E.Shannon, Holly C.Hunsberger, AlessiaMastrodonato, MichelleStackmann, Josephine C.McGowan, GillesRubinstenn, Christine A.Denny.


Major depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects. Here, we characterized a novel NMDA receptor antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior.


Saline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus was quantified with immunohistochemistry or Western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu ammonis 3 (vCA3) 1 week after injection.


Given after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPA receptor–mediated bursts in vCA3, indicating a common neurobiological mechanism for further study.


Our results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM’s mechanism of action with the goal of clinical development.

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FENM attenuates learned fear and protects against stress-induced behavioral despair when administered 1 week before CFC. (A) Experimental protocol. (B) Freezing was comparable across all groups during CFC training. (C, D) (R,S)-ketamine (30 mg/kg) and FENM (20 and 30 mg/kg) significantly decreased fear expression. (E) On FST day 1, memantine (10 mg/kg) significantly increased immobility time when compared with saline-administered mice. (F, G) On day 2 of the FST, (R,S)-ketamine and FENM (20 and 30 mg/kg) significantly reduced immobility time when compared with saline controls. (H–J) In the OF, (R,S)-ketamine and FENM did not alter distance traveled or time spent in the center of the arena. (K) In the MB task, all groups buried a comparable number of marbles. (L, M) (R,S)-ketamine and FENM did not alter distance traveled or time spent in the open arms and center of the EPM. (N) Memantine, (R,S)-ketamine and FENM did not alter latency to feed in the NSF. (O) Memantine significantly reduced latency to feed in the HC during the NSF. (P) Food eaten in the NSF was comparable across all drug groups. n = 5–12 male mice per group; error bars represent ± SEM; ∗p < .05, ∗∗p < .01, ∗∗∗p < .001. CFC, contextual fear conditioning; EPM, elevated plus maze; FENM, fluoroethylnormemantine; FST, forced swim test; HC, home cage; K, (R,S)-ketamine; M, memantine; MB, marble burying; NSF, novelty-suppressed feeding; OF, open field; Sal, saline.