Cannabinoid effects on sustained conductances that control neuronal excitability have not been investigated in brain. Here, intracellular voltage-clamp recordings were performed using the rat hippocampal slice preparation to study the postsynaptic effect of cannabinoid agonists on CA1 pyramidal neurons. Superfusion of the cannabimimetics WIN55212-2 or methanandamide onto CA1 neurons elicited an inward steady-state current that reversed near the equilibrium potential for K(+) and voltage-dependently activated from a threshold of approximately -70 mV. The cannabinoid receptor (CB1) antagonist SR141716 did not alter membrane properties but prevented this effect. Further investigation 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 blocker linopirdine. Assessment of the I(M) relaxation indicated that cannabinoids decreased I(M) in a concentration-dependent manner, with a maximum inhibition of 45 +/- 3% with WIN55212-2 (EC(50) of 0. 6 microM) and 41 +/- 5% with methanandamide (EC(50) of 1 microM). Cannabinoids did not affect the inwardly rectifying cationic h-current (I(h)). The cannabinoid-induced I(M) decrease was prevented by SR141716 but remained unaffected by the muscarinic receptor antagonist atropine. Conversely, the cholinergic agonist carbamylcholine decreased I(M) in the presence of SR141716, indicating that cannabinoid and muscarinic receptor activation independently diminish I(M). It is concluded that cannabinoids may postsynaptically augment the excitability of CA1 pyramidal neurons by specifically decreasing the persistent voltage-dependent I(M).