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Significance Lipid transmitters, such as endocannabinoid and eicosanoids, play important roles in the nervous system and regulate behaviors that include pain, emotionality, and addiction. Chemical probes that perturb lipid transmitter biosynthesis are needed to understand the functions of these pathways in the nervous system. Here, we describe selective and in vivo active inhibitors of the diacylglycerol lipases DAGLα and DAGLβ, which biosynthesize the endocannabinoid 2-arachidonoylglycerol (2-AG). We show that these inhibitors produce rapid and dramatic changes in a brain lipid signaling network, comprising not only 2-AG, but also eicosanoids and diacylglycerols. These lipid changes are accompanied by impairments in synaptic plasticity and attenuation of neuroinflammatory responses in vivo, underscoring the broad role that DAGLs play in nervous system metabolism and function.

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition