Abuse of synthetic
cannabinoids is a serious social problem worldwide. Intentional ingestion of synthetic
cannabinoids can cause severe toxicity, including
seizures. Here we investigated the effects of acute administration of synthetic
cannabinoids on the induction of epileptic
seizures by monitoring electroencephalographic activity in freely moving mice. The synthetic
cannabinoid,
AM2201, induced abnormal, high-amplitude (>2-fold baseline amplitude), sharp-wave activity. The abnormal spike-wave discharges were accompanied by epileptiform behavior: rigid posture, tail extension, rearing with forepaws extended, jumping, and intermittent tonic-clonic jerking movements. The abnormal spike-wave discharges and behavioral changes were suppressed by pretreatment with the selective
CB1 receptor antagonist
AM251, but not with the selective
CB2 receptor antagonist
AM630 or the
vanilloid receptor antagonist,
capsazepine. Furthermore, the group 1
metabotropic glutamate receptor antagonist
SIB1757 eliminated AM2201-induced spike-wave discharges and episodes of epileptiform behavior.
AM2201 markedly increased the extracellular
glutamate concentration in the hippocampus during periods of AM2201-induced abnormal spike-wave discharges and behavioral changes. These findings are the first evidence that
AM2201 induces epileptic
seizures by enhancing glutamatergic transmission in the hippocampus. Our findings demonstrate that induction of epileptic
seizures by synthetic
cannabinoids is mediated by CB1 receptors, but not by CB2 receptors, and further suggest that rapid elevation of glutamatergic transmission may play an important role in the induction of
seizures following intentional ingestion of synthetic
cannabinoids.