Several lines of evidence suggest that cannabinoid compounds
are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid
system in regulating seizure activity has not been tested in an in
vivo model of epilepsy that is characterized by spontaneous,
recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract 9- tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6Hpyrrolo[3,2,1-i,j]quinolin-6-one [R()WIN55,212 (5 mg/kg)],
completely abolished spontaneous epileptic seizures. Conversely,
application of the cannabinoid CB1 receptor (CB1) antagonist,
N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-
methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A),
significantly increased both seizure duration and frequency. In
some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical
condition status epilepticus. Furthermore, we determined that
during an short-term pilocarpine-induced seizure, levels of the
endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate
not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the
CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was
significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a
role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs
with epilepsy.
