Figure 4. Antidepressant actions of NV-5138 are dependent on activation of mTORC1 signaling.

(A) Rats were administered vehicle or NV-5138 (160 mg/kg) and PFC dissections were collected 1 hour later. (B) Diagram showing postsynaptic signaling. Levels of the phosphorylated and activated forms of (C) mTOR, (D) p70S6K, and (E) 4EBP1 as determined by Western blot analysis were increased by NV-5138 and ketamine; levels of total proteins or GAPDH were also measured to control for loading differences. Results are shown as mean ± SEM. n = 6/group. *P < 0.05; **P < 0.01, Student’s t test. (F) Rats were implanted with bilateral cannula in the mPFC and allowed to recover for approximately 2 weeks. (G) The mTORC1 inhibitor rapamycin was infused into the mPFC 30 minutes prior to administration of vehicle or NV-5138. Twenty-four hours after NV-5138 administration, behavioral studies were initiated and conducted over the next 3 days (H–K). NV-5138 treatment significantly decreased immobility time and latency to feed, but these effects were blocked by rapamycin in (H) the FST (F_2,17 = 20.46, P < 0.001) and (J) the NSFT (F_2,17 = 5.36, P < 0.05), respectively. No significant effects were seen in (I) LMA (F_2,17 = 0.200, P > 0.05) or (K) HCF (F_2,17 = 0.814, P > 0.05). Results are shown as mean ± SEM. n = 6–7. *P < 0.05; **P < 0.01, Tukey’s multiple comparisons test, following significant results of 1-way ANOVA. Rap, rapamycin.