In this study, the effects of methohexital are compared on the voltage-gated sodium (Na+) and potassium ion (K+) conductances of Retzius cells in the leech Macrobdella and of dorsal root cells of the chick in culture. Under current-clamp conditions methohexital prolonged the Na+-dependent action potential of neurons in the leech. This prolongation occurred in the absence of changes in resting membrane potential or the maximum rate of depolarization of the spike. The prolonged action potentials were identical to those recorded in the same neurons in the absence of outward currents [i.e. in Ca2+-free Ringer's solution containing Mn2+, tetraethylammonium chloride (TEA) and 4-aminopyridine (4-AP)]. They consisted of an initial spike, followed by a plateau lasting several hundreds of milliseconds. Both components of the action potential were Na+-dependent and resistant to tetrodotoxin (TTX), while the plateau was selectively blocked by saxitoxin (STX), suggesting that it originated from the flow of Na+ through a conductance different from that underlying the spike potential (Johansen and Kleinhaus, 1987). Similarly, the plateau of the action potential prolonged by methohexital, described in this study was abolished by 50 microM saxitoxin. These results suggest that the action of the drug resulted from a block of repolarizing K+-conductances. This was confirmed by voltage-clamp experiments which showed that methohexital (100-1000 microM) reduced both IK and IA in the Retzius cell, essential mimicking the combined effects of TEA and 4-AP (Johansen and Kleinhaus, 1986b). In contrast, in dorsal root cells, methohexital decreased the amplitude of Na+ and K+ currents equally. This modulation of ionic conductances by methohexital may be important for the sedative and anesthetic actions of the drug.