In vitro and in vivo effects of the anorectic agent dexfenfluramine on the central serotoninergic neuronal systems of non-human primates. A comparison with the rat.
The effects of repeated subcutaneous (s.c) injections of dexfenfluramine (d-F; 10 mg/kg, twice daily, for 4 days) on the contents of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brain were assessed in primates (cynomolgus and rhesus monkeys) and compared with the regional brain concentrations of unchanged drug and its active metabolite, dexnorfenfluramine (d-NF). This four-day, high-dose, regimen caused a large depletion of 5-HT (more than 95%) and of 5-HIAA (80-90%) in all brain areas studied (cortex, hippocampus, putamen, caudate nucleus and hypothalamus) 2 h after the last injection of d-F. Analysis of the plasma and brain contents of d-F and d-NF confirmed that both compounds were concentrated as in other species, in regions of the primate brain. However, d-NF was concentrated to a greater extent than d-F, and there were differences between the two primate species. Unlike in the rat brain, concentrations of d-NF greatly exceeded those of d-F in the primate brain suggesting that in these primates the d-NF may play a major role in the overall neurochemical response. The effects of d-F and d-NF on different in vitro parameters of serotoninergic neuronal function did not show appreciable differences between cynomolgus or rhesus monkeys when compared to rats, the ability of the two compounds to inhibit 5-HT reuptake, to enhance its release, and to affect the binding of [3H] -d-F or of [3H] -mesulergine (a ligand for 5-HT2C receptors) being similar. Kinetic differences in the disposition of d-F appear to have more relevance than biochemical effects in providing an explanation for the more marked brain depletion induced by d-F in primates than in rodents.
Mennini
T
T
Instituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Fracasso
C
C
Cagnotto
A
A
Bergami
A
A
Frittoli
E
E
Gobbi
M
M
Caccia
S
S
Garattini
S
S
D000818:Animals; D001067:Appetite Depressants / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D005277:Fenfluramine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009642:Norfenfluramine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000032:analysis* / Q000378:metabolism / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000032:analysis*; D013045:Species Specificity
D001067:Appetite Depressants; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin