Effects of 2-arachidonylglycerol, an endogenous cannabinoid, on neuronal activity in rat hippocampal slices

The monoacylglycerol 2-arachidonylglycerol is an endogenous ligand of canna binoid receptors. We examined whether 2-arachidonylglycerol can influence e xcessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpos e, the effects of 2-arachidonylglycerol were compared with those of the syn thetic cannabinoid agonist WIN 55,212-2. At concentrations of 10-50 mu M, 2-arachidonylglycerol attenuated the ampli tude of the orthodromic population spike and the slope of the field excitat ory postsynaptic potential (field EPSP). However, the effect of the synthet ic cannabinoid WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)met hyl]pyrrolol[1,2,3-de]-1,4-benzoxazinyl]-(1 -naphthalenyl)methanone; 0.1 mu M and 1 mu M) was significantly higher than that of the endogenous ligand. At a concentration of 1 mu M, WIN 55,212-2 completely suppressed the field EPSP. However, none of the investigated compounds did affect the presynapt ic fiber spike of the afferents. The CB1 receptor antagonist SR 141716 (N-p iperidino-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-3-pyrazole-carb oxamide blocked the inhibition evoked by the cannabinoids. Both 2-arachidonylglycerol (30 mu M) and WIN 55,212-2 (100 nM) shifted the input-output curve of the postsynaptic spike and the field EPSP to the righ t and increased the magnitude of paired-pulse facilitation, indicating a pr esynaptic mechanism of action. 2-Arachidonylglycerol and WIN 55,212-2 attenuated the frequency of spontane ously occurring epileptiform burst discharges in CA3 elicited by omission o f Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these ca nnabinoids was blocked by SR 141716. In conclusion, 2-arachidonylglycerol seems to limit neuronal excitability v ia cannabinoid receptors of the CB1 type. By acting predominantly at a pres ynaptic site, it is capable of reducing excitatory neurotransmission, a mec hanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.