Effect of thymoleptics on fenfluramine-induced depletion of brain serotonin in rats

Ghezzi, D.; Samanin, R.; Bernasconi, Sergio; Tognoni, Gianni; Gerna, M.; Garattini, Silvio

doi:10.1016/0014-2999(73)90073-3

Cited by 63 publications

(10 citation statements)

References 13 publications

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“…Fenfluramine produces a long-lasting depletion of brain 5-HT by promoting the release of 5-HT from its storage sites (Fuxe et aL, 1975;Kannengiesser et al, 1976). Since the 5-HTdepleting action of fenfluramine is antagonized by pretreatment with strong 5-HT uptake blockers, like chlorimipramine (Ghezzi et al, 1973), fenfluramine probably uses the membrane-bound amine uptake system ('membrane pump') to enter the 5-HT neurones. The lack of efficacy of nomifensine in counteracting the effect of fenfluramine in vivo indicates that the new antidepressant does not exert a significant effect on 5-HT re-uptake in the brain.…”

Section: Resultsmentioning

confidence: 99%

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Studies on brain metabolism of biogenic amines.

Schacht¹,

Leven²,

Bäcker³

1977

Brit J Clinical Pharma

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Section: Resultsmentioning

confidence: 99%

“…Strong inhibitors of 5-HT up-take markedly antagonize the decrease in brain 5-HT induced by fenfluramine (Ghezzi et al, 1973).…”

Section: Introductionmentioning

confidence: 92%

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Studies on brain metabolism of biogenic amines.

Schacht¹,

Leven²,

Bäcker³

1977

Brit J Clinical Pharma

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“…In fact the inhibitory effect on uptake together with the releasing action may also explain the reduction in brain 5-HIAA levels caused by fenfluramine (Duhault & Verdavainne, 1967), since it is believed that 5-HT is chiefly deaminated intraneuronally (Blaschko & Levine, 1966). The inhibition of 5-HT uptake is not sufficient alone to lower brain 5-HT or 5-HIAA (Carlsson, Corrodi, Fuxe & Hokfelt, 1969;Ghezzi et al, 1973), unless there is a concomitant release of 5-HT, as for instance during electrical stimulation of the midbrain raphe . The possibility that the inhibition of 5-HT uptake and the release of 5-HT may be important factors in the reduction of brain 5-HT produced by fenfluamine is, in any case, reinforced by other experimental studies showing that this anorectic drug does not inhibit tryptophan hydroxylase, monoamine oxidase (Morgan, Lofstrandh & Costa, 1972) or 5-HT synthesis (Costa et al, 1971).…”

Section: Discussionmentioning

confidence: 99%

Effect of Fenfluramine on 5‐hydroxytryptamine Uptake and Release by Rat Blood Platelets

Buczko

Gaetano

Garattini

1975

British J Pharmacology

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(+)‐Fenfluramine reduces the central stores of 5‐hydroxytryptamine (5‐HT) by a poorly understood mechanism. Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings. (+)‐Fenfluramine shows a dual effect: it inhibits the uptake of [14C]‐5‐HT by platelets and it releases newly absorbed [14C]‐5‐HT from platelets. The inhibition of [14C]‐5‐HT uptake induced by (+)‐fenfluramine appears very rapidly, is concentration‐dependent and seems not to be competitive. (+)‐Fenfluramine is ten times less effective than chloroimipramine but ten times more effective than (+)‐amphetamine; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolite norfenfluramine ((+)‐ or (‐)‐form). The release of [14C]‐5‐HT from platelets induced by (+)‐fenfluramine is concentration‐dependent but increases with increased incubation time. Both chloroimipramine and (+)‐amphetamine are in comparison very poor release inducers; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolites. The effect on [14C]‐5‐HT uptake exerted by (+)‐fenfluramine and chloroimipramine in vitro could not be observed in vivo. The observed effect of fenfluramine on the uptake and release of 5‐HT may explain the lowering action of fenfluramine on the brain 5‐HT level, an effect considered of importance for the anorectic effect of this drug.

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“…Both noradrenaline (Weissman, Koe & Tenen, 1966) and dopamine (Kruk, 1973) have been suggested as intermediates in the anorectic effects of amphetamine. On the other hand, it has been suggested that the mediator for fenfluramine is 5-hydroxytryptamine (Jespersen & Scheel-Kruiger, 1970; Funderburk, Hazelwood, Ruckart & Ward, 1971; Samanin, Ghezzi, Valzelli & Garattini, 1972;Clineschmidt, 1973;Ghezzi, Samanin, Bernasconi, Tognoni, Gerna & Garattini, 1973). The biochemical action of fenfluramine is not, however, confined to the serotoninergic nerve terminal, since fenfluramine has also been shown to affect noradrenaline concentrations, both centrally and peripherally (Costa,40 Groppetti & Revuelta, 1971; Sipes, Ziance & Buckley, 1971;Ziance, Sipes, Kinnard & Buckley, 1972;Mitchell & Mottram, 1976).…”

Section: Introductionmentioning

confidence: 99%

The Sympathomimetic Activity of Fenfluramine Hydrochloride on Rat Vas Deferens

Mottram

Wadhwani

1977

British J Pharmacology

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The peripheral, pharmacological effects of the anorexigenic agent, fenfluramine hydrochloride, have been investigated on rat isolated vas deferens. Characteristic spiked contractions were observed within 2 to 3 min after exposure to fenfluramine; these contractions reached a rate of around 13 per min and were of variable height. Pre‐treatment of vasa with the indirectly acting sympathomimetic amine, tyramine, greatly reduced both the height and rate of contraction induced by fenfluramine. The uptake inhibitor, desipramine, required a concentration in excess of 10 μM to affect fenfluramine‐induced contractions. Effects of desipramine on fenfluramine contractions were of equal magnitude whether desipramine was administered before fenfluramine or at the height of the fenfluramine‐induced contractions. Pre‐treatment with debrisoquine (0.5 mM), reduced the contractions in response to fenfluramine over a period of time. Fenfluramine, added to vasa from rats which had been injected intraperitoneally with 5 mg/kg reserpine 24 h and 48 h previously, failed to induce its characteristic contractions. It is concluded that fenfluramine can be classed as an indirectly acting sympathomimetic amine on peripheral adrenergic nerve terminals.

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Effect of thymoleptics on fenfluramine-induced depletion of brain serotonin in rats

Cited by 63 publications

References 13 publications

Studies on brain metabolism of biogenic amines.

Studies on brain metabolism of biogenic amines.

Effect of Fenfluramine on 5‐hydroxytryptamine Uptake and Release by Rat Blood Platelets

The Sympathomimetic Activity of Fenfluramine Hydrochloride on Rat Vas Deferens

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