Depression is second most disabling disease and leading cause of suicidality worldwide¹. Popular antidepressants developed based on monoamine theory have limitations of low recovery rate and long remission time². Ketamine, an NMDA receptor antagonist, has been shown to restore behavioral phenotype and brain energy metabolism in social defeat model of depression³. However, its use as antidepressant is limited due to addictive and psychotomimetic properties⁴. Lanicemine (AZD6765), a low trapping NMDA channel blocker, is safer in comparison with ketamine⁵. However, very little information is available for its antidepressant mechanism. The major objective of the current study was to evaluate effects of lanicemine on behavior and neurometabolism in chronic unpredictable mild stress (CUMS) model of depression.All animal experiments were performed under approved protocols by the Institutional Animal Ethics Committee of CCMB. C57BL/6J mice (2 month old) were divided into following groups: (A) Control + Normal Saline (Cont + NS, n=6); (b) Control + Lanicemine (Cont + Azd, n=6); (c) CUMS + Normal Saline (Cums + NS, n=6); (d) CUMS + Lanicemine (Cums + Azd, n=6). Group (c) and (d) mice were subjected to CUMS paradigm for 21 days by subjecting them to varieties of stress twice daily for three weeks⁶. At the end of the CUMS protocol, mice in Group (b) and (d) received lanicemine (1.5 mg/kg, i.p.) thrice in a week for 2 weeks, while that in Group (a) and (c) received 0.25 ml normal saline (0.9% NaCl) for the same duration. Depression phenotype was evaluated by sucrose preference⁷ and forced swim test⁸. For assessment of metabolic activity, urethane (1.5 g/kg, i.p.) anesthetized mice were infused with [1,6-¹³C_²]glucose for 10 min, and head was frozen in liq. nitrogen. Metabolites were extracted from frozen prefrontal cortical tissue. The concentration and ¹³C labeling of metabolites were measured in ¹H-[¹³C]-NMR spectra of tissue extracts recorded at 600 MHz Bruker Avance II NMR spectrometer⁹. The cerebral metabolic rates of glucose oxidation by glutamatergic and GABAergic neurons in prefrontal cortex were determined from the ¹³C labeling of amino acids from [1,6-¹³C₂]glucose¹⁰.Mice exposed to CUMS paradigm exhibit significant reduction in sucrose preference (Cont + NS: 84.1±4.3 %, CUMS + NS: 62±2.5 %, p<0.01), and increase in immobility time in forced swim test (Cont + NS: 33.7±2 s, CUMS + NS: 80.8±3 s, p<0.01). The lanicemine treatment in CUMS mice was able to restore sucrose preference, and immobility time to the control values (Fig. 1). The ¹³C labeling of glutamate-C4 (p<0.01), GABA-C2 (p<0.01), glutamine-C4 (p<0.01) and aspartate-C3 (p<0.05) was decreased significantly in CUMS mice (Fig. 2, Table 1). The reduction in ¹³C labeling of amino acids from [1,6-¹³C₂]glucose indicates decreased metabolic activity of glutamatergic (CUMS: 0.19±0.02; Cont: 0.28±0.02 μmol/g/min, p<0.01) and GABAergic neurons (CUMS: 0.04±0.003; Cont: 0.07±0.003 μmol/g/min, p<0.01) in CUMS mice (Fig. 3). Interestingly, lanicemine intervention for two weeks period restored the amino acids labeling to the control values (Fig. 2, Table 1). Additionally, the cerebral metabolic rates of glucose oxidation by glutamatergic (CUMS + lanicemine: 0.29±0.01; Cont + lanicemine: 0.29±0.01 μmol/g/min, p=0.89) and GABAergic neurons (CUMS + lanicemine: 0.06±0.004; Cont + lanicemine: 0.06±0.001 μmol/g/min, p=0.89) were found to be restored to the control levels after lanicemine intervention (Fig. 3). These data provide an experimental evidence for the restoration of behavioral phenotype, and activity of excitatory and inhibitory neurons with lanicemine in depression. Further, investigations on astroglial metabolic activity may be useful to elaborate the detailed mechanism of action of lanicemine.