ANORECTIC EFFECT AND BRAIN CONCENTRATIONS OF D-FENFLURAMINE IN THE MARMOSET - RELATIONSHIP TO THE INVIVO AND INVITRO EFFECTS ON SEROTONERGIC MECHANISMS

The present study investigated the anorectic activity of d-fenfluramine (d-F) and the relationship with brain levels of unchanged drug and its metabolite d-norfenfluramine (d-NF) in marmosets, relating them to neurochemical effects on the serotoninergic system. d-F and d-NF were equally active in reducing food intake (ED50 about 3 mg/kg, p.o.). However, the brain concentrations of the metabolite required to reduce food intake after synthetic d-NF were more than twice those after d-F, indicating that d-NF contributes to but does not completely explain the anorectic effect of d-F. At this dose d-F did not appreciably modify the serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) contents of the brain regions examined, except for a slight enhancement of 5-HIAA in hippocampus. In vitro in brain cortical synaptosomes d-F inhibited [H-3]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [H-3]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [H-3]5-HT. Like in other species the marmoset too has saturable and specific [H-3]d-F binding sites, for which d-NF has lower affinity. d-F and d-NF have low affinities for 5-HT receptor subtypes, except that d-NF has appreciable affinity for 5-HT1C and 5-HT1D receptors. Unlike in rodents but similarly to primates in the striatum the pharmacology of 5-HT receptors seems to correspond to the 5-HT1D subtype. Brain concentrations of d-F and d-NF at anorectic doses exceeded the concentrations required in vitro to influence the serotoninergic system. Therefore the effect of d-F on food intake might possibly be explained by an interaction with the 5-HT system, particularly uptake and release mechanisms, and that of d-NF by an action on 5-HT1C and 5-HT1D receptor subtypes.