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A second endogenous cannabinoid that modulates long-term potentiation

Abstract

Cannabinoid receptors are molecular targets for marijuana and hashish, the widespread drugs of abuse. These receptors are expressed in areas of the central nervous system that contribute in important ways to the control of memory, cognition, movement and pain perception1. Indeed, such functions can be strongly influenced by cannabinoid drugs, with consequences that include euphoria, analgesia, sedation and memory impairment2. Although the pharmacology of cannabinoid drugs is now beginning to be understood, we still lack essential information on the endogenous signalling system(s) by which cannabinoid receptors are normally engaged. An endogenous ligand for cannabinoid receptors, anandamide, has been described3. Here we report that sn-2 arachidonylglycerol (2-AG), a cannabinoid ligand isolated from intestinal tissue4, is present in brain in amounts 170 times greater than anandamide. 2-AG is produced in hippocampal slices by stimulation of the Schaffer collaterals, an excitatory fibre tract that projects from CA3 to CA1 neurons. Formation of 2-AG is calcium dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase. 2-AG activates neuronal cannabinoid receptors as a full agonist, and prevents the induction of long-term potentiation at CA3–CA1 synapses. Our results indicate that 2-AG is a second endogenous cannabinoid ligand in the central nervous system.

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Figure 1: Identification of 2-arachidonylglycerol (2-AG) in rat brain by GC/MS.
Figure 2: Neural activity stimulates 2-AG production in hippocampal slices.
Figure 3: Ca2+-dependence, cellular localization and role of PLC and DAG lipase activities in 2-AG formation.
Figure 4: Activation of neuronal CB1 receptors by 2-AG.
Figure 5: 2-AG prevents the induction of LTP.

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Acknowledgements

We thank G. R. Siggins for use of equipment (funded by NIMH), S. Madamba for technical help, and P. Magistretti, M. Beltramo and A. Giuffrida for reading the manuscript critically. This research was supported by the Neurosciences Research Foundation, which receives major support from Novartis, and by a scientist development award from the National Institute of Drug Abuse (to P.S.).

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Correspondence to Daniele Piomelli.

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Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation . Nature 388, 773–778 (1997). https://doi.org/10.1038/42015

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