Exposure to hyperbaric oxygen (OHP) (60 psig) produced convulsions, and elevation in weight, water content and hemoglobin content of the lung and post-exposure delayed lethality. Pretreatment with pargyline, succinic acid or ascorbic acid provided protection against all of the above effects of OHP toxicity. In OHP exposed mice there was a decrease in brain γ-aminobutyric acid (GABA) levels concomitant with an inhibition of its synthesizing enzyme, glutamic acid decarboxylase, without any effect on the activity of its catabolizing enzyme GABA transaminase (GABA-T). Both pargyline and succinic acid produced an increase in GABA levels in the mice exposed to room air at normal pressure, and prevented the OHP-induced decrease in GABA. Pargyline treatment inhibited GABA-T activity without altering the activity of GAD. Conversely, succinic acid increased the activity of both GAD and GABA-T and prevented the OHP-induced decrease in GAD activity. Ascorbic acid was without effect on any of the components of the GABA system and it did not prevent any of the OHP-induced alterations in GABA or GAD. Brain ammonia levels are increased in the OHP exposed mice with a concomitant decrease in the glutamine levels. All three agents protected the OHP-exposed mice against these OHP-induced alterations. There data are consonant with the hypothesis that decreased brain GABA and increased brain ammonia levels are involved in the etiology of OHP toxicity.