Administration ofd-tubocurarine (dTC) or diphenylhydantoin (DPH) was evaluated as a pretreatment to prevent succinylcholine (Sch) evoked fasciculations. Experiments were designed to determine the nature of the drug–drug interactions, sites of interaction, and site of fasciculation suppression. Sch is known to evoke repetitive discharge generation by motor nerve terminals (MNTs). Transmission of these prejunctional discharges causes fasciculations. A cat solcus neuromuscular preparationin situ, which enables recording of nerve action potentials initiated by MNTs, their transmitted muscle action potentials, and the resultant contractile responses, was used to explore Sch effects before and after iv pretreatment withdTC or DPH.dTC is known to act prejunctionally to suppress repetitive discharges initiated by facilitatory drugs and tetanic conditioning of MNTs. Accordingly, pretreatment withdTC 50 μg · kg-1suppressed the Sch-induced MNT repetitive discharging and correspondingly suppressed generalized fasciculations without affecting twitch. ThisdTC dose, however, also reduced Sch blocking potency by 33%, slowed its rate, and shortened block duration. These latter effects represent competitive postjunctional antagonism. DPH is also known to suppress MNT repetitive discharging. Correspondingly, Sch-induced repetitive firing and ensuing fasciculations were suppressed by DPH (30 mg · kg-1) without affecting twitch. UnlikedTC, this DPH dose increased Sch blocking potency by 50%, increased the initial rate of block, and did not alter block duration. These DPH effects were dose-dependent and within the anticon-vulsant range for cats. Therefore, patients with anticonvulsant levels of DPH may not require pretreatment before Sch. It is concluded that the effectiveness of a pretreatment regimen for prevention of Sch fasciculations depends on a prejunctional suppression of repetitive firing generated by MNTs. The cat solcus preparation serves as a clinically relevantin situmethod for evaluating prejunctional and postjunctional effects of drugs and should serve as a reliable test for other pretreatment candidates.