Daily administration of convulsive doses of pentetrazole in dogs resulted in a decrease in the seizure threshold and development of increasingly severe clonic-tonic convulsions. Concomitantly, the concentration of ?-aminobutyric acid (GABA) in cisternal cerebrospinal fluid (CSF) was markedly reduced, whereas plasma GABA levels were not altered. When re-tested after a 3-week resting period, animals were found to have retained their increased seizure sensitivity and reduction in CSF GABA levels. ?-Acetylenic GABA and phenobarbital in doses antagonizing the establishment of increased convulsive sensitivity in response to repeated pentetrazole injections also counteracted the fall in CSF GABA. Valproic acid proved less effective to influence the convulsive response of continued pentetrazole administration. The data suggest that a functional deficit in the GABA system may underlie the persistent changes in seizure susceptibility observed.