Nature Neuroscience 8, 1139–1141 (2005); Published online 7 August 2005

Our paper identified 6-methyl-2-p-tolylaminobenzo[d]oxazin-4-one (URB754; Specs) as a monoacylglycerol lipase (MGL) inhibitor that enhances hippocampal depolarization-induced suppression of inhibition (DSI). However, in subsequent tests of non-commercial URB754, we failed to replicate these results, suggesting that a bioactive impurity was present in the commercial material. We have identified this impurity as bis(methylthio)mercurane (Supplementary Results online). Because this compound interacts with multiple targets, we tested another MGL inhibitor, methylarachidonylfluorophosphonate (MAFP), which prolonged DSI (Fig. 1), confirming that monoacylglycerol lipase contributes to the termination of DSI, as others have reported1. Another generation of endocannabinoid metabolism inhibitors is needed to test this hypothesis further.

Figure 1: Effects of MAFP on DSI in hippocampal CA1 pyramidal cells.
figure 1

Top, traces from a representative experiment showing the effects of vehicle (ethanol, 0.00003%) or MAFP (Tocris, 45 nM) on the transient reduction of spontaneous inhibitory postsynaptic potentials (IPSCs) elicited by a depolarizing stimulus (arrow). Scale bars, 100 pA, 5 s. Bottom left, averaged time-course of DSI after administration of vehicle (solid squares) or MAFP (open squares). Bottom right, DSI area in the first 30 s after stimulus application was significantly larger in MAFP-treated than in control slices.

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Note: Supplementary information is available on the Nature Neuroscience website.