Introduction: Our aim was to determine if a reduction of serotonin (5-HT) synthesis in the brain would provide any protection from the behavioral alterations induced by hippocampal brain-damage. The development of open-field activity (5 minute sessions) over two weeks and the acquisition of a passive avoidance task were chosen for study. Methods: There were 3 groups of lesioned rats - those hippocampal aspiration lesions, those with only damage to the neocortex overlying the hippocampus, and a sham-operated group. Half of each group was treated 300 mg/kg p-chlorphenylalanine (PCPA) for 3 successive days to deplete levels of 5-HT and the other half were given the saline vehicle alone. [Hippocampal damage is associated with increased activity in the open field and impaired learning of the step-through passive avoidance response.] Results: 1/ Animals with hippocampal damage became hyperactive in the second week after operation. 2/ PCPA treatment had no effect on locomotion, (nor on the frequently observed thigmotaxic nature of the behavior) 3/ Rearing was initially depressed after the operation, and PCPA treatment facilitated its recovery - but PCPA decreased rearing in intact animals during the second week of testing. 4/ Reduced levels of grooming were seen in hippocampal animals, while PCPA reduced grooming in those with neocortical damage 5/ The animals with hippocampal damage were impaired in witholding response in the passive avoidance task - those treated with PCPA performed even worse in not witholding the shock-reinforced step-through response. This contrasted with the intact animals, where PCPA treatment reduced the amount of footshock the animals were exposed to in the task. Conclusions: The results are consistent with a role for mesolimbic 5-HT innervation of the dorsal hippocampus having an influence on novelty-elicited responses (e.g. grooming in home vs. novel cage and investigative rearing behavior) and in modulation of the sensitivity of response to electric footshock (hypersensitive in PCPA-intact animals, hyposensitive in PCPA-hippocampal animals).