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Effect of escalating doses of d-fenfluramine on the content of indoles in brain.
Neuropharmacology. 1992 Sep; 31(9):875-9.N

Abstract

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.

Authors+Show Affiliations

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

1436395

Citation

Caccia, S, et al. "Effect of Escalating Doses of D-fenfluramine On the Content of Indoles in Brain." Neuropharmacology, vol. 31, no. 9, 1992, pp. 875-9.
Caccia S, Sarati S, Anelli M, et al. Effect of escalating doses of d-fenfluramine on the content of indoles in brain. Neuropharmacology. 1992;31(9):875-9.
Caccia, S., Sarati, S., Anelli, M., & Garattini, S. (1992). Effect of escalating doses of d-fenfluramine on the content of indoles in brain. Neuropharmacology, 31(9), 875-9.
Caccia S, et al. Effect of Escalating Doses of D-fenfluramine On the Content of Indoles in Brain. Neuropharmacology. 1992;31(9):875-9. PubMed PMID: 1436395.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of escalating doses of d-fenfluramine on the content of indoles in brain. AU - Caccia,S, AU - Sarati,S, AU - Anelli,M, AU - Garattini,S, PY - 1992/9/1/pubmed PY - 1992/9/1/medline PY - 1992/9/1/entrez SP - 875 EP - 9 JF - Neuropharmacology JO - Neuropharmacology VL - 31 IS - 9 N2 - 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. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/1436395/Effect_of_escalating_doses_of_d_fenfluramine_on_the_content_of_indoles_in_brain_ DB - PRIME DP - Unbound Medicine ER -