We examined rapid effects of neuregulin (NRG) on nicotinic acetylcholine (ACh) receptors in interneurons located in the stratum radiatum of the hippocampus. Two types of response were detected by whole-cell recordings after brief pulses of ACh. One type was a rapidly rising and falling (monophasic) current that was blocked by methyllycaconitine. The other type was a similar fast response followed by a more slowly rising and falling current. The slow component of the biphasic response was resistant to methyllycaconitine. Perfusion or local application with NRG 1beta rapidly decreased fast inward ACh currents. NRG 1beta had no effect on slow responses. NRG 1beta suppression was abolished by the ErbB tyrosine kinase inhibitor PD 158780 (4-[(3-bromophenyl) amino]-6-(methylamino)-pyrido[3,4-d]pyridimine). The NRG 1beta effect was also inhibited by phalloidin and cytochalasin D. Furthermore, NRG 1beta decreased the number of surface Alexa Fluor 488 alpha-bungarotoxin binding sites. We believe that the NRG 1beta-induced inhibition of ACh currents is because of receptor internalization trigged by protein tyrosine phosphorylation. Significantly, fast nicotinic EPSCs evoked in the presence of muscarinic, ionotropic glutamate, and GABA receptors antagonists were also reduced by NRG 1beta. Thus, short-term as well as long-term effects of NRG must be taken into consideration in studies of ACh receptor-mediated synaptic efficacy in the CNS.