Although our biochemical data indicate that 2-AG is elevated by repeated restraint stress, it is possible that the enhanced DSI observed in stressed mice could be related to increased CB1 receptor signaling, rather than increased in eCB production. To examine this possibility directly, we determined the effects of the CB1 receptor agonist Win 55212-2 on GABAergic transmission in control and stressed mice. In control mice, Win 55212-2 suppressed eIPSC amplitude to 47.3 ± 4.0% of baseline (N = 5; Figure 7). In mice exposed to 10 days of restraint stress, Win 55212-2 suppressed eIPSC amplitude to 66.2 ± 9.1% of baseline, N = 5. Two-way ANOVA showed a significant effect of repeated stress (p < 0.0001), time (p < 0.0001), but no interaction. These data indicate that repeated restraint stress decreases CB1 receptor sensitivity, indicating the enhanced DSI is not mediated increased CB1 receptor signaling.
