The long-recognized but poorly understood convulsant effects of d-tubocurarine (d-TC), the classic blocker of peripheral nicotinic synapses, were examined and compared to those produced by the convulsants, bicuculline and picrotoxin. Extracellular and intracellular recordings were made in the CA3 region of guinea pig hippocampal slices maintained in vitro. After the slices were exposed to micromolar concentrations of bath-applied d-TC, epileptiform activity, consisting of bursts of repetitive field potentials, occurred spontaneously or in response to orthodromic stimulation of the mossy fibers. Intracellular recordings demonstrated that the d-TC-induced extracellular field responses were correlated with a large membrane depolarization or paroxysmal depolarizing shift (PDS). This event was determined to be synaptic in character since a) its amplitude was a monotonic function of membrane potential, b) it could be inverted in polarity with depolarization, and c) its frequency of occurrence was independent of membrane potential. Spontaneous inhibitory postsynaptic potentials (IPSPs) were identified by depolarizing cells to 0 mV. These spontaneous IPSPs were abolished by d-TC. The effects of d-TC on the responses produced by γ-aminobutyric acid (GABA) were investigated. The GABA-mediated decreases in input resistance were plotted as a function of the log of the charge delivered to the GABA-containing pipette. The resultant charge-response curves were sigmoidal and were shifted to the right by bath-applied d-TC or bicuculline. In contrast, the convulsant, picrotoxin, produced a complex form of antagonism, consisting of a decrease in the maximum response along with a shift to the right in the GABA charge-response curve. Several known nicotinic and muscarinic blockers were also applied to the slices. None of these agents induced epileptiform activity. The results are consistent with the hypothesis that d-TC interferes with the function of GABA, an important inhibitory neurotransmitter in the hippocampus, and that this action is implicated in the observed epileptiform behavior.