(A) Plasma concentration (ng/ml) of ISRIB after a single intraperitoneal injection (5 mg/kg). Plasma was collected at the indicated times and the concentration was determined by mass spectrometry (mean ± SEM, N = 3). (B) Brain (ng/g tissue) and plasma concentrations (ng/ml) of ISRIB after a single intraperitoneal injection (2.5 mg/kg). Data (mean ± SEM, N = 3) were obtained at the indicated times. (C) Escape latencies are significantly shorter in mice treated with ISRIB. Data (mean ± SEM) were obtained in a weak 5 days-long training session in the hidden platform version of the Morris water maze (1 trial per day). Mean escape latencies were plotted as a function of training days in mice treated with ISRIB (closed squares, N = 8) or vehicle (open circles N = 8) (*p<0.05). Mice were injected daily with ISRIB immediately after training. (D) After completion of training in the study shown in panel (A), mice treated with ISRIB (black column) showed a significant preference for the target quadrant (*p<0.05). The probe test was performed 24 hr after the last training session. p values are derived from a two-tailed Student’s t test for unpaired samples. (E) After completion of training in the study shown in panel a, mice treated with ISRIB (black column) increased the number of times they crossed the platform location as compared to the vehicle-treated mice (grey column) (*p<0.05). p values are derived from a two-tailed Student’s t test for unpaired samples. (F) Systemic administration of ISRIB (intraperitoneally after training) enhances long-term contextual fear memory (right bars, 24 hr), while it does not affect short-term memory (left bars, 1 hr) (N = 10 per group, *p<0.05). Data are presented as mean ± SEM. (G) Auditory fear conditioning is enhanced in rats treated with ISRIB. Freezing in response to a tone was assessed 3 hr (short-term memory, STM, left panel) and 24 hr (long-term memory, LTM, right panel) after training (vehicle-treated N = 8, and ISRIB-treated N = 7) after tone presentation (CS) and before tone presentation (pre-CS). For these experiments vehicle or ISRIB was infused directly by cannula into the amygdala after training. ISRIB-infused rats show increase freezing at 24 hr (*p<0.05).