Effects of 2-arachidonylglycerol, an endogenous cannabinoid, on neuronal activity in rat hippocampal slices.
The monoacylglycerol 2-arachidonylglycerol is an endogenous ligand of cannabinoid receptors. We examined whether 2-arachidonylglycerol can influence excessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpose, the effects of 2-arachidonylglycerol were compared with those of the synthetic cannabinoid agonist WIN 55,212-2. At concentrations of 10-50 microM, 2-arachidonylglycerol attenuated the amplitude of the orthodromic population spike and the slope of the field excitatory postsynaptic potential (field EPSP). However, the effect of the synthetic cannabinoid WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone; 0.1 microM and 1 microM) was significantly higher than that of the endogenous ligand. At a concentration of 1 microM, WIN 55,212-2 completely suppressed the field EPSP. However, none of the investigated compounds did affect the presynaptic fiber spike of the afferents. The CB1 receptor antagonist SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-3- pyrazole-carboxamide) blocked the inhibition evoked by the cannabinoids. Both 2-arachidonylglycerol (30 microM) and WIN 55,212-2 (100 nM) shifted the input-output curve of the postsynaptic spike and the field EPSP to the right and increased the magnitude of paired-pulse facilitation, indicating a presynaptic mechanism of action. 2-Arachidonylglycerol and WIN 55,212-2 attenuated the frequency of spontaneously occurring epileptiform burst discharges in CA3 elicited by omission of Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these cannabinoids was blocked by SR 141716. In conclusion, 2-arachidonylglycerol seems to limit neuronal excitability via cannabinoid receptors of the CB1 type. By acting predominantly at a presynaptic site, it is capable of reducing excitatory neurotransmission, a mechanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.
Ameri
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Institute of Pharmacology, Toxicology and Natural Products, University of Ulm, Germany.
Simmet
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D000700:Analgesics / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D004558:Electric Stimulation; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009281:Naphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D000077285:Rimonabant
D000700:Analgesics; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; D018377:Neurotransmitter Agents; D010880:Piperidines; D011720:Pyrazoles; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant