Fig. 1.

Timelines of behaviors elicited by high-dose JZL184 (40 mg/kg) in wild-type mice (top row) and FAAH(−/−) mice (bottom row). Simultaneous FAAH and MAGL blockade produces enhanced effects that undergo tolerance following repeated JZL184 administration. JZL184 increases tail withdrawal latency (left column) compared with vehicle, an effect whose magnitude is enhanced and prolonged in FAAH(−/−) mice. Similar enhanced effects are seen in FAAH(−/−) mice in hyper-reflexive responses (middle column) and biting responses (right column) when undergoing catalepsy testing in the bar test. All behavioral responses undergo significant tolerance following repeated administration of JZL184 for 6 days. **P < 0.01; ***P < 0.001 versus all other treatment groups; n = 8 per group.