Increased serotonin (5-hydroxytryptamine, 5-HT) release in the hippocampus induced by repeated stress is thought to be critical for the neuroadaptation that alleviates the adverse effects of stressors on emotion and behavior. A failure in this process may be one of the primary neuropathological mechanisms underlying the development of stress-related disorders. The para-chloroamphetamine (p-PCA) was used to deplete 5-HT in the rat prior to repeated restraint stress (6h/day for 10 days), and determined the consequences of 5-HT depletion on stress-induced alterations of animal behaviors, hippocampal corticosteroid receptor immunoreactivity and the brain-derived neurotrophic factor (BDNF) mRNA expression. Behavioral tests indicate that the stressed rats with 5-HT depletion showed pronounced anxiety, reduced reward sensitivity and enhanced learned-helplessness. In addition, they also developed learning impairments in Morris water maze tests. These results suggest that hippocampal 5-HT depletion compromised adaptation to chronic stress. Furthermore, repeated stress caused a lesser degree of glucocorticoid receptor increase and down-regulation of BDNF mRNA. The study suggest that 5-HT deficiency in the adult hippocampus may impair stress adaptation by suppressing hippocampal GR and BDNF expression.