Effect of escalating doses of d-fenfluramine on the content of indoles in brain.
The neurochemical effects of a large dose challenge (5 mg/kg, i.p.) of d-fenfluramine (d-F) in rats, given saline or gradually escalating doses of d-F (0.1-2.5 mg/kg, i.p.), were examined with regard to regional sensitivity and the time-course of recovery. The indole-depleting effect after the large dose of d-F to saline-pretreated animals appeared to differ, depending on the areas of brain considered (cortex greater than hippocampus greater than striatum), despite the fact that the drug and its main metabolite, d-norfenfluramine (d-NF) distributed almost uniformly in the regions of brain examined. The depletion in all these regions of the brain was reversible within 6 weeks, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) being back to control levels in the hippocampus and striatum but not 5-HT in the cortex. However, when rats were exposed to gradually escalating doses of d-F the recovery of indoles in the brain, after injection of the large dose challenge, appeared to be faster. Indoles were markedly less reduced 1 week later in the cortex, hippocampus and striatum, with content of indole in the striatum showing complete recovery and the long-term depletion of 5-HT and 5-HIAA, by the subsequent large dose challenge was almost completely reversed in all regions. Analysis of the concentrations of d-F and its main metabolite d-fenfluramine (d-NF) in brain excluded any pharmacokinetic tolerance. These results suggest that during therapeutic treatment with d-F, the use of escalating doses may attenuate the potential for the long-lasting decrease of 5-HT in brain.
Caccia
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Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Sarati
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S
Anelli
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M
Garattini
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S
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D005277:Fenfluramine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism*; D008297:Male; D009642:Norfenfluramine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D007211:Indoles; D009642:Norfenfluramine; D005277:Fenfluramine