Hippocampal corticosteroid receptors are regulated by corticosterone as well as by neurotransmitters, such as serotonin (5-HT). Studies have demonstrated that long-term changes in 5-HT levels are associated with alterations in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) number. However, the effect of short-term manipulations of 5-HT levels on hippocampal corticosteroid receptor levels has not been thoroughly investigated. The present set of studies examined the effect of para-chloroamphetamine (PCA) administration on both short-term and long-term regulation of hippocampal 5-HT and corticosteroid receptor levels. PCA is a selective serotonergic neurotoxin which initially releases 5-HT to cause a short-term depletion of 5-HT stores, followed by a long-term decrease in 5-HT levels which presumably reflects the destruction of 5-HT nerve terminals. In the initial study rats were adrenalectomized and 24 h later injected with PCA (20 mg/kg) and sacrificed 3 h later. PCA produced a large decrease in hippocampal 5-HT (-79%) and 5-hydroxyindoleacetic acid (5-HIAA) (-40%) concentrations. In addition, PCA significantly decreased both hippocampal GR (-28%) and MR (-35%) levels. Pretreatment with fluoxetine (20 mg/kg), which presumably blocks the uptake of PCA into 5-HT nerve terminals, completely blocked the PCA-induced decreases in both 5-HT and corticosteroid receptor concentrations. In a final experiment, the long-term (7 days) effect of PCA administration on hippocampal 5-HT and corticosteroid receptor levels was examined. PCA (10 mg/kg given on 2 consecutive days) was administered to adrenal-intact rats which were adrenalectomized 6 days later and subsequently sacrificed following a 24 h interval. PCA produced an 87% decrease in hippocampal 5-HT and 5-HIAA levels, but did not alter hippocampal GR or MR levels.(ABSTRACT TRUNCATED AT 250 WORDS)