The
anticonvulsant properties of marijuana have been known for centuries. The recently characterized endogenous
cannabinoid system thus represents a promising target for novel
anticonvulsant agents; however, administration of exogenous
cannabinoids has shown mixed results in both human
epilepsy and animal models. The ability of
cannabinoids to attenuate release of both excitatory and inhibitory
neurotransmitters may explain the variable effects of
cannabinoids in different models of
epilepsy, but this has not been well explored. Using acute mouse brain slices, we monitored field potentials in the CA1 region of the hippocampus to characterize systematically the effects of the
cannabinoid agonist WIN55212-2 (WIN) on evoked basal and epileptiform activity. WIN, acting presynaptically, significantly reduced the amplitude and slope of basal field excitatory postsynaptic potentials as well as stimulus-evoked epileptiform responses induced by omission of
magnesium from the extracellular
solution. In contrast, the combination of omission of
magnesium plus elevation of
potassium induced an epileptiform response that was refractory to attenuation by WIN. The effect of WIN in this model was partially restored by blocking γ-
aminobutyric acid type B (
GABA(B) ), but not
GABA(A) , receptors. Subtle differences in models of epileptiform activity can profoundly alter the efficacy of
cannabinoids. Endogenous
GABA(B) receptor activation played a role in the decreased
cannabinoid sensitivity observed for epileptiform activity induced by omission of
magnesium plus elevation of
potassium. These results suggest that interplay between presynaptic
G protein-coupled receptors with overlapping downstream targets may underlie the variable efficacy of
cannabinoids in different models of
epilepsy.