Anorectic effect and brain concentrations of D-fenfluramine in the marmoset: relationship to the in vivo and in vitro 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 [3H]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [3H]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [3H]5-HT. Like in other species the marmoset too has saturable and specific [3H]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.(ABSTRACT TRUNCATED AT 250 WORDS)
Caccia
S
S
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Anelli
M
M
Fracasso
C
C
Frittoli
E
E
Giorcelli
P
P
Gobbi
M
M
Taddei
C
C
Garattini
S
S
Mennini
T
T
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002144:Callithrix; D004435:Eating / Q000187:drug effects; D005277:Fenfluramine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009642:Norfenfluramine / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism
D011985:Receptors, Serotonin; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin