p-Chloroamphetamine-induced hyperthermia pharmacologically distinct from fenfluramine-induced hyperthermia

The influence of various drug pretreatments upon the responses of rabbits to the putative indirect 5-hydroxytryptaminergic agonists p-chloroamphetamine (PCA) and fenfluramine were examined. In naive rabbits PCA evoked hyperthermia, behavioural excitation and prominent forepaw clonic activity, while fenfluramine produced only hyperthermia and behavioural stimulation. The hyperthermic and behavioural responses of both agents were reduced by the 5-hydroxytryptamine (5-HT) uptake inhibitor, fluoxetine, potentiated by the monoamine oxidase inhibitor, pheniprazine, and unaltered by the dopaminergic antagonist, haloperidol. Pretreatment with the 5-hydroxytryptaminergic receptor blockers cinanserin, cyproheptadine or D-2-bromolysergic acid diethylamide markedly attenuated the effects of fenfluramine but only slightly influenced the responses to PCA. Depeletion of central 5-HT stores with p-chlorophenylalanine also affected responses to fenfluramine more than responses to PCA. The tryptaminergic receptor blocker methergoline abolished both PCA-induced hyperthermia and forepaw clonus--but not behavioural stimulation--while the effects of flenfluramine were only partly reduced. We interpret these data to mean that PCA- and fenfluramine-induced drug effects have different underlying mechanisms, the PCA responses relying possibly upon tryptamine while the fenfluramine responses are 5-hydroxytryptaminergic.