A. Ameri et al., Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices, BR J PHARM, 126(8), 1999, pp. 1831-1839
1 The arachidonic acid derivative arachidonylethanolamide (anandamide) is a
n endogeneous ligand of cannabinoid receptors that induces pharmacological
actions similar to those of cannabinoids such as Delta(9)-tetrahydrocannabi
nol (THC). We examined whether anandamide can influence excessive neuronal
activity by investigating stimulation-induced population spikes and epilept
iform activity in rat hippocampal slices. For this purpose, the effects of
anandamide were compared with those of the synthetic cannabinoid agonist WI
N 55,212-2 and its inactive S(-)-enantiomer WIN 55,212-3.
2 Both anandamide (1 and 10 mu M) and WIN 55,212-2 (0.1 and 1 mu M) decreas
ed the amplitude of the postsynaptic population spike and the slope of the
field excitatory postsynaptic potential (field e.p.s.p.) without affecting
the presynaptic fibre spike of the afferents. At a concentration of 1 mu M,
WIN 55,212-2 completely suppressed the postsynaptic spike, whereas the S(-
)-enantiomer WIN 55,212-3 produced only a slight depression. The CBI recept
or antagonist SR 141716 blocked the inhibition evoked by the cannabinoids.
SR 141716 had a slight facilitatory effect on neuronal excitability by itse
lf.
3 Anandamide shifted the input-output curve of the postsynaptic spike and t
he field e.p.s.p. to the right and increased the magnitude of paired-pulse
facilitation indicating a presynaptic mechanism of action.
4 Anandamide and WIN 55,212-2, but not WIN 55,212-3, attenuated both stimul
us-triggered epileptiform activity in CA1 elicited by omission of Mg2+ and
spontaneously occurring epileptiform activity 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.
5 In conclusion, cannabinoid receptors of the CB1 type as well as their end
ogeneous ligand, anandamide, are involved in the control of neuronal excita
bility, thus reducing excitatory neurotransmission at a presynaptic site, a
mechanism which might be involved in the prevention of excessive excitabil
ity leading to epileptiform activity.