Cannabinoids decrease the K+ M-current in hippocampal CA1 neurons

Cannabinoid effects on sustained conductances that control neuronal excitab ility have not been investigated in brain. Here, intracellular voltage-clam p recordings were performed using the rat hippocampal slice preparation to study the postsynaptic effect of cannabinoid agonists on CA1 pyramidal neur ons. Superfusion of the cannabimimetics WIN55212-2 or methanandamide onto C A1 neurons elicited an inward steady-state current that reversed near the e quilibrium potential for K+ and voltage-dependently activated from a thresh old of approximately -70 mV. The cannabinoid receptor (CB1) antagonist SR14 1716 did not alter membrane properties but prevented this effect. Further i nvestigation revealed that the inward current elicited by cannabinoids was caused by a decrease of the noninactivating voltage-dependent K+ M-current (I-M). Cannabinoids had no effect in slices pretreated with the M-channel b locker linopirdine. Assessment of the I-M relaxation indicated that cannabi noids decreased I-M in a concentration-dependent manner, with a maximum inh ibition of 45 +/- 3% with WIN55212-2 (EC50 of 0.6 mu M) and 41 +/- 5% with methanandamide (EC50 of 1 mu M). Cannabinoids did not affect the inwardly r ectifying cationic h-current (I-h). The cannabinoid-induced I-M decrease wa s prevented by SR141716 but remained unaffected by the muscarinic receptor antagonist atropine. Conversely, the cholinergic agonist carbamylcholine de creased I-M in the presence of SR141716, indicating that cannabinoid and mu scarinic receptor activation independently diminish I-M. It is concluded th at cannabinoids may postsynaptically augment the excitability of CA1 pyrami dal neurons by specifically decreasing the persistent voltage-dependent I-M .