5, p = 0.03) relative to the EC which showed no increase following ketamine (Figures 5A and 5B). To determine whether increases in extracellular glutamate were necessary for ketamine-evoked hippocampal hypermetabolism to occur, we pretreated mice with LY379268 (10 mg/kg), a drug that reduces neuronal glutamate release through activation of presynaptic mGlur2/3 receptors (Lorrain et al., 2003; Monn et al., 1999). Mice were pretreated for 5 days with LY379268 or saline prior to recording Docetaxel solubility dmso the extracellular glutamate response or CBV response to acute ketamine challenge 30 mg/kg.

An ANOVA revealed that L379268 blocked the ketamine-evoked glutamate elevation in CA1/SUB (F1,11 = 5.5, p = 0.04; Figure 5C). At this glutamate-suppressing dose, LY379268 also prevented ketamine-induced increases in CA1/SUB CBV (overall F2,27 = 21.7, p < 0.001); planned comparisons of LY379268 to SAL pretreatment (p < 0.001; Figure 5D). To determine whether glutamate mediated the induction of the hypermetabolic LY294002 price state and relative volume loss observed with repeated intermittent ketamine exposure, mice were administered either saline or LY379268 (10 mg/kg) 1 hr prior to receiving each ketamine (16 mg/kg) treatment, totaling 12 (3 weekly) cotreatments over 1 month. Prior to endpoint CBV and structural hippocampal imaging, all animals were withdrawn from treatment for 48 hr. LY739268 prevented ketamine-induced

basal increases in CBV throughout the trisynaptic circuit and subiculum (DG F1,17 = 7.0, p = 0.01; CA3 F1,17 = 5.2, p = 0.04; CA1 F1,17 = 4.3, p = 0.05; SUB F1,17 = 6.1, p = 0.03; Figure 6A). At this basal hypermetabolism-suppressing dose, LY379268 also prevented the

repeated ketamine-induced hippocampal volume decrease over the Rolziracetam 1 month exposure (F1,17 = 11.7, p = 0.003; Figure 6B). Additional morphometric analyses revealed that the region showing the most consistent relative protection overlapped with mid-body CA1 and subiculum (Figure 6C). This was consistent with the post-mortem analysis (performed as described above) which showed an effect of LY379268 cotreatment on hippocampal structure following repeated ketamine (Figure 6D). Specifically, while there were no group differences observed in the rostrodorsal hippocampus, the size of the caudoventral hippocampus was larger in repeated ketamine-treated mice receiving LY379268 co-treatment than mice co-treated with saline (t12 = 2.1, one-tailed p < 0.05). To further investigate circuit mediators of the above effects of repeated ketamine, we quantified the density of the parvalbumin-positive (PV+) subpopulation of GABAergic interneurons in the CA fields of three groups from the longitudinal treatment studies (saline/saline [saline control], saline/ketamine 16 mg/kg, LY379268 10 mg/kg/ketamine 16 mg/kg). A general linear model showed significant differences in PV+ cell density across treatment groups (Wald chi-square [df = 2] = 8.1, p < 0.05).