Neurones in deeper layers of slices of temporal or frontal human neocortex maintained in vitro were impaled with microelectrodes and responses to cholinergic agonists were studied under current and voltage clamp conditions. A range of membrane currents were identifiable: inactivating and persistent Na(+)-conductances, inactivating and persistent Ca2(+)-conductances, two types of inward currents activated by hyperpolarization (IQ and If.i.r.) and voltage and Ca2(+)-activated K(+)-conductances, which were distinguished on the grounds of their characteristic voltage or pharmacological specificity. The cholinergic agonists muscarine or carbachol were applied in the medium superfusing the slices. Two major effects were observed: consistently, the time and voltage-dependent noninactivating K(+)-conductance IM was suppressed and, when Ca2(+)-influx was permitted (in the absence of Ca2(+)-channel blockers), a Ca2(+)-activated K(+)-conductance was transiently or persistently potentiated. Consistent with a suppression of IM, muscarine excited human neocortical neurones only when applied during a period of membrane depolarization to a potential at which IM would be expected to exert a braking effect on excitability. Applied at a potential negative to the M-current activation range, muscarine had no excitatory or even an inhibitory effect on the cell. Collectively, these results demonstrate that in the human, IM can be a target for cholinergic regulation and, in addition, complex effects of ACh on other conductances could modulate cell firing patterns.