The effect of pentobarbital (PB) and related compounds on frog motoneurons was examined with sucrose gap recording from the ventral roots. PB was found to: (1) depress the action of glutamate, (2) selectively enhance the action of GABA, (3) reverse the non-competitive picrotoxin antagonism of GABA and the competitive strychnine antagonism of beta-alanine, but not the competitive bicuculline methiodide antagonism of GABA, and (4) elicit a GABAmimetic hyperpolarization. The first three actions had a threshold concentration of 10 microM, while the GABAmimetic action required a 10-fold higher concentration. The reversal of picrotoxin's action by PB suggests that PB might modify GABA mechanisms by combining to the picrotoxin recognition site. Phenobarbital shared all of the properties of PB but was approximately one-fifth as potent. The only property that phenytoin shared with PB was a weak depression of glutamate responses. Chlordiazepoxide selectively enhanced GABA responses but was devoid of the other actions of PB. These results suggest that the GABAmimetic effect of PB may be an important feature in the depressant and anesthetic properties of PB. The anesthetic chloralose, which is structurally unrelated to PB, nevertheless shared all of the actions of PB. This finding suggests that the properties described for PB may also be found in other general anesthetics.