The pre- and postjunctional effects of the lincosamide antibiotics, clindamycin and lincomycin, were studied in voltage-clamped transected twitch fibers of costocutaneous muscles of garter snakes (species Thamnophis). Miniature end-plate currents and end-plate currents (EPCs) were recorded over a wide voltage range for each antibiotic. The amplitude and kinetics of these currents were studied and estimates of the quantal content of evoked transmitter release determined. High concentrations of clindamycin (2 X 10(-4) M) and lincomycin (2 X 10(-3) M) produced significant depression of EPC amplitude and a nonlinearity in the EPC-voltage relationships. The time constant of EPC decay was accelerated in clindamycin and the relationship between the time constant of EPC decay and membrane potential remained a single exponential function with a concentration-dependent loss of the voltage dependence. In contrast to clindamycin, lincomycin produced biphasic EPCs which consisted of two components, one faster and one slower than the control decay rate. The relative amplitude and decay rate of each component was both concentration and voltage dependent. Either increasing the concentration of lincomycin or membrane hyperpolarization decreased the amplitude ratio, iota slow/iota fast, and increased the ratio of the respective time constants, tau slow/tau fast. Clindamycin affected EPC decay amplitude and quantal content in the same concentration range, whereas lincomycin affected EPC decay at concentrations 20 times less than those required to reduce EPC amplitude and quantal content. These results suggest that the neuromuscular blocking effects of clindamycin involve both pre-and postjunctional sites, whereas the effects of lincomycin are primarily on the postjunctional receptor-channel complex.