The 5-HT antagonists ketanserin, mianserin, methysergide, and cyproheptadine and the 5-HT uptake inhibitors fluoxetine and zimeldine were evaluated for their ability to protect against an hypoxia-induced performance deficit in a passive avoidance (PA) task. The ability to retain a PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% O2. The 5-HT2 selective antagonists ketanserin (0.01-10.0 mg/kg SC) and mianserin (0.05-10.0 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to a 6.5% oxygen environment. Peak effective doses (PED) for ketanserin and mianserin were 3.0 mg/kg SC and 0.05 mg/kg SC, respectively. In contrast, methysergide (0.05-30.0 mg/kg SC) and cyproheptadine (0.05-7.0 mg/kg SC), antagonists that show less affinity for the 5-HT2 receptor subtype, were not effective in preventing the hypoxia-induced amnesia. Inhibition of 5-HT reuptake by fluoxetine (0.01-1.0 mg/kg SC) produced dose-dependent increases in retention latencies with a PED of 0.05 mg/kg SC while zimeldine (0.1-10.0 mg/kg SC), another 5-HT reuptake inhibitor, had no effect on the amnesia. The results of this study suggest that modification of 5-HT after exposure to hypoxia can ameliorate a performance deficit in an animal model of learning and memory.