Abstracts

RATIONALE: Although only one cannabinoid receptor (CB1), located on GABAergic terminals, has been identified in the brain, its absence does not eliminate cannabinoid signaling at glutamatergic synapses. Cannabinoid pharmacology at excitatory synapses is not well characterized. Current evidence indicates that postsynaptic calcium entry is required for cannabinoid synthesis and release. Since CA3 interictal activity results in a large postsynaptic calcium influx in CA3 cells, we investigated the effects of cannabinoid signaling in our preparation.
METHODS: We tested the effects of cannabinoid antagonist AM251 (2 [mu]M), and of cannabinoid uptake inhibitor AM404 (20 [mu]M), on the CA3 synchronized network activity using extracellular and intracellular recordings. Hippocampal coronal slices were prepared from 4-6 week old Sprague-Dauley rats. Spontaneous bursting of the CA3 network was induced by blockade of GABA[sub]A[/sub] and [sub]B[/sub] conductances with 100 [mu]M picrotoxin and 1[mu]M CGP55845A, respectively.
RESULTS: Cannabinoid antagonism increases the frequency of CA3 interictal activity by 30% (n=4). Additionally, cannabinoid uptake inhibition results in large decreases in the duration of CA3 bursts (30%, n=5), paired in 40% of cases with large decreases in CA3 burst frequency. Comparison of mEPSCs[ssquote] amplitude distributions before and after application of the cannabinoid uptake antagonist AM404 indicates that endogenous cannabinoids selectively affect the probability of multivesicular release but not univesicular release at recurrent collateral synapses.
CONCLUSIONS: These data suggest that endogenous cannabinoids have an anticonvulsant effect on CA3 synchronized activity. By selectively affecting the probability of multivesicular glutamate release but not univesicular release at recurrent collateral synapses, endogenous cannabinoids decrease the extent of synchronized CA3 network activity.
[Supported by: NIH]