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  • 1
    Electronic Resource
    Electronic Resource
    Anorectic effect and brain concentrations of D-fenfluramine in the marmoset: relationship to the in vivo and in vitro effects on serotonergic mechanisms (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 347 (1993), S. 306-312 
    Details
    ISSN: 1432-1912
    Keywords: d-Fenfluramine ; d-Norfenfluramine ; Marmoset ; Anorectic ED50 ; Effects on serotoninergic mechanisms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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-HT1Cand 5-HT1Dreceptors. 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167450
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    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 (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 641-647 
    Details
    ISSN: 1432-1912
    Keywords: Dexfenfluramine ; Dexnorfenfluramine ; Primates ; Brain uptake and distribution ; Brain indoles ; 5-HT uptake and release ; 5HT2c receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167183
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 22-28 
    Details
    ISSN: 1432-1912
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties, citalopram (10 mg/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg/kg, p.o. twice a day for 21 days, 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of brain 5-HT uptake (sites) were found by measuring functional [3H]5-HT uptake and [3H]citalopram binding in cortical and hippocampal synaptosomes, and by [3H]citalopram binding autoradiography in the raphe nuclei (5-HT cell bodies) and the ventral tegmental area (5-HT axonal pathway). Chronic treatments had no effect on presynaptic 5-HT1B autoreceptors, functionally evaluated by measuring 5-HT1B-mediated inhibition of depolarization-induced [3H]5-HT release from cortical and hippocampal synaptosomes. Chronic citalopram or fluoxetine did not significantly affect the binding of [3H]BRL-43694 to 5-HT3 receptors in the rat brain cortex. Citalopram had no effect on [125I]SB-207710 binding to 5-HT4 receptors, measured by autoradiography in the substantia nigra. Negative results, such as those reported in the present study, could be due to a number of variables including the animal species, the treatment schedule or the brain areas considered, thus explaining the differences from some previous reports of significant effects of SSRI. However, our negative data are in agreement with many other published studies, suggesting that adaptive modifications of brain 5-HT transporters, terminal 5-HT1B receptors, 5-HT3 and 5-HT4 receptors may not be a general effect induced by all SSRI.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005024
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 343 (1991), S. 483-490 
    Details
    ISSN: 1432-1912
    Keywords: d-Fenfluramine ; Anorectics ; Rats ; Mice ; Guinea pigs ; Serotonin ; Serotonin receptors ; Serotonin uptake ; Serotonin release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present study compares the anorectic activity of d-fenfluramine and its metabolite d-norfenfluramine in three animal species. d-Fenfluramine and d-norfenfluramine show anorectic activity at increasing doses (ED50) in rats, guinea pigs, and mice, d-norfenfluramine being more active than d-fenfluramine in all three species. Equiactive anorectic activities are reached with different brain levels of d-fenfluramine and d-norfenfluramine, guinea pigs being the most sensitive species, followed by rats then mice. The metabolite most probably plays a major role in the anorectic effect of d-fenfluramine in guinea pigs, contributes to the anorectic activity in rats, but adds little to the action of the parent drug in mice. The different sensitivity to d-fenfluramine and d-norfenfluramine in these three species does not appear to be explained by a number of biochemical parameters, including serotonin uptake or release, receptor subtypes, or 3H-d-fenfluramine binding and uptake.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169550
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    Paper (German National Licenses)
    Fulltext
  • 5
    Electronic Resource
    Electronic Resource
    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 (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 641-647 
    Details
    ISSN: 1432-1912
    Keywords: Key words Dexfenfluramine ; Dexnorfenfluramine ; Primates ; Brain uptake and distribution ; Brain indoles ; 5-HT uptake and release ; 5HT2C receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  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 neuro- nal 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167183
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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