N-alcohols exert a dual action on neuronal nicotinic acetylcholine (ACh) receptors with short-chain alcohols exhibiting potentiating action and long-chain alcohols exhibiting inhibitory action. n-Butanol lies at the transition point from potentiation to inhibition. To elucidate the mechanism of dual action of alcohols, the effects of n-butanol on the human alpha4beta2 ACh receptors expressed in the HEK293 cell line were analyzed in detail by the whole-cell patch-clamp technique. Prolonged applications of n-butanol evoked small currents with an EC(50) value of 230 +/- 90 mM and a Hill coefficient of 1.8 +/- 0.4. This current was blocked by either the ACh channel blocker mecamylamine or the receptor blocker dihydro-beta-erythroidine, indicating that butanol activated receptors as a partial agonist. As expected from its partial agonist action, n-butanol also modulated ACh-induced currents in a concentration-dependent manner. Butanol at 300 mM potentiated currents induced by low concentrations of ACh (</=30 microM), while inhibiting the currents induced by high concentrations of ACh (100-3,000 microM). In addition, butanol at a low concentration (10 mM) suppressed the currents evoked by 10 to 3,000 microM ACh, a result consistent with a channel-blocking action. Most features of n-butanol effects were satisfactorily simulated by a model in which butanol acts as a partial agonist and as a channel blocker.