CANNABINOIDS MODULATE POTASSIUM CURRENT IN CULTURED HIPPOCAMPAL-NEURONS

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significan ce. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neuron s from hippocampus, a brain region that exhibits high cannabinoid rece ptor density. The electrophysiological effects of cannabinoids were de termined by whole-cell patch clamp recordings of voltage-dependent pot assium currents. The voltage dependence of the rapidly inactivating po tassium A current (I(A)), characteristic of hippocampal neurons, was s ignificantly altered in a concentration-dependent manner by cannabinoi d analogs. Decreased inactivation, which led to an increased activatio n of I(A) near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on I(A) while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid a nalogs was similar to that observed with respect to binding at cannabi noid receptors in brain membranes. The concentration-related effective ness of cannabinoid analogs in modulating I(A) was similar to their po tency in stimulating low K(m) GTPase in cell membranes isolated from t he cannabinoid receptor-rich dentate gyrus. These data support the con clusion that cannabinoid effects on I(A) are mediated through G-protei n-coupled receptors. This cannabinoid-induced shift in the voltage dep endence of I(A) could serve to counteract fast, transient, depolarizin g events such as action potentials and synaptic currents in hippocampa l neurons.