The effects of ATP (adenosine 5' triphosphate) analogs on gross cochlear potentials and single primary afferent discharge properties were studied by intracochlear perfusion in anesthetized guinea pigs. ATP-gamma-S was most potent, with betagammamethylene-ATP and Bz-ATP being significantly less effective. These data are consistent with the notion that purinergic receptors activated by scala tympani perfusion contain subunits of the P2X(2) variant. The relative ineffectiveness of Bz-ATP (a P2X(7) agonist) suggests that while this variant has been reported to be expressed in the cochlea, it may not play a major functional role under normal conditions. Changes in the threshold of the gross DC receptor potential (summating potential, SP) and the compound action potential (CAP) were consistent with a combination of effects on both early and final stages of the transduction process, as reported by previous workers. Effects of ATP-gamma-S on single-neuron spontaneous firing rates varied according to the initial spontaneous rate of each primary afferent. Effects on single-neuron tuning curves were consistent with an action mainly on the outer hair cell transduction with betagammamethylene-ATP (elevation of tuning curve tips), but with ATP-gamma-S changes in sensitivity across the full extent of the tuning curve indicated an additional action on inner hair cell-afferent neurotransmission. In agreement with previous reports on ATP-gamma-S, it was found that all ATP analogs produced significant increases in the DC potential in scala media (endocochlear potential, EP). However, the relationship between changes in EP (a major component of the driving force on ions through hair cells) and the alterations in gross and single unit measures of cochlear activity was not clear. (C) 2003 Elsevier B.V. All rights reserved.