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The phytocannabinoid cannabidiol (CBD) is at the forefront of therapeutic cannabinoid research due to its non-psychotropic properties. Research supports its use in a variety of disorders, yet the cellular mechanisms of its action remain unclear. In this study, the effect of CBD upon Ca2 homeostasis in hippocampal cells was characterised. CBD (1 [mu]M) elevated intracellular Ca2 ([Ca2 ]i) by ~ 45% of basal Ca2 levels in both glia (77% responders) and neurones (51% responders). Responses to CBD were reduced in high excitability HEPES buffered solution (HBS), but not affected in low excitability/low Ca2 HBS. CBD responses were also significantly reduced (by 50%) by the universal Ca2 channel blocker cadmium (50 [mu]M) and the L-type specific Ca2 channel blocker nifedipine (20 [mu]M). Interestingly, intracellular store depletion with thapsigargin (2 [mu]M) had the most dramatic effect on CBD responses, leading on average to a full block of the response. Elevated CBD-induced [Ca2 ]i responses (> 100%) were observed in the presence of the CB1 receptor antagonist, AM281 (1 [mu]M), and the vanilloid receptor antagonist, capsazepine (CPZ, 1 [mu]M). Overall, our data suggest that CBD modulates hippocampal [Ca2 ]i homeostasis via intracellular Ca2 stores and L-type VGCC-mediated Ca2 entry, with tonic cannabinoid and vanilloid receptor signalling being negatively coupled to this pathway.

(C) 2006Elsevier, Inc.