The inhibitory actions of picrotoxin (PTX) and zinc on the GABAC receptor in acutely isolated catfish cone horizontal cells were studied and compared using the whole-cell patch clamp technique. PTX blocked the GABAC current elicited by 30 microM GABA with IC50 = 0.64 microM. Over a PTX concentration range of 1-100 microM, simultaneous application of PTX with GABA (30 microM) produced current transients at both the onset and offset of the drug pulse. When the PTX concentration was maintained before, during, and after GABA application, the current transients at the onset and offset of GABA application disappeared. Thus, these transients seem to reflect a slower initial action of PTX at, and faster washout of PTX from, the GABAC receptor than GABA when they were co-applied. The full recovery from PTX inhibition required a second GABA application. Recovery could not be achieved by a prolonged wash in the absence of GABA. These results suggest that PTX effect is use-dependent. Zinc also potently blocked the GABAC current elicited by 30 microM GABA with an IC50 about an order of magnitude higher than that of PTX (IC50 = 8.2 microM). However, only the onset, but not the offset current transient was observed when zinc was simultaneously applied with GABA. The full recovery of the GABAC current from zinc inhibition was obtained after washing for 20 sec and did not require a subsequent GABA application. This indicates that the zinc effect is use-independent. Our findings suggest that: (1) the zinc binding site is on the surface of the GABAC receptor molecule; (2) there is a PTX binding site that is probably inside the receptor and its access requires GABA binding to the receptor.