Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)