Fenfluramine, p-chloroamphetamine and p-fluoroamphetamine stimulation of pituitary-adrenocortical activity in rat: evidence for differences in site and mechanism of action.

Serum corticosterone concentrations were measured in rats after injection of fenfluramine (FEN), p-chloroamphetamine (PCA) and p-fluoroamphetamine (PFA), halogenated amphetamine derivatives believed to exert their behavioral and physiological effects through the release and/or depletion of brain serotonin (5-HT). Animals were pretreated with various serotonergic drugs before FEN, PCA or PFA in order to ascertain the role of 5-HT in mediating the pituitary-adrenocortical response to each compound. Systemic administration of FEN, PCA or PFA caused a dose-dependent corticosterone elevation, with a potency rank ordering of PCA greater than FEN greater than PFA. Chronic depletion of brain 5-HT by pretreatment with p-chlorophenylalanine or 5,7-dihydroxytryptamine antagonized the PCA-induced elevation, but not that produced by FEN or PFA. When injected i.c.v., PCA and PFA elevated corticosterone levels whereas FEN did not. The central PCA-induced elevation was prevented by pretreatment with either the 5-HT reuptake inhibitor fluoxetine or the 5-HT receptor blocker methysergide. Fluoxetine or methysergide also antagonized the corticosterone elevation produced by systemically injected PCA or FEN, but not that produced by PFA. In the final experiment, pretreatment with dexamethasone, an inhibitor of pituitary adrenocorticotropic hormone secretion, prevented the corticosterone elevation produced by all three drugs. Thus, despite their structural and pharmacological similarities, FEN, PCA and PFA each act differently to stimulate corticosterone secretion. As expected, PCA elevates corticosterone levels through a central serotonergic mechanism that requires the continued synthesis and storage of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)