Fenfluramine, either as a racemic (d,l) mixture, or the dextro (d) isomer, has been widely used as a 5-HT challenge although its future use is in question following its withdrawal due to potential cardiac problems.26 In spite of some concerns about the 5-HT-specificity of d,l-fenfluramine, responses to both formulations of fenfluramine appear qualitatively similar.27 d-Fenfluramine affects 5-HT neurotransmission in a number of ways. It is a 5-HT-releasing agent, a process requiring uptake via the 5-HT transporter, it blocks 5-HT reuptake and its metabolite d-norfenfluramine is believed to stimulate postsynaptic 5-HT2C
receptors.28 Administration to humans stimulates PRL and ACTH/cortisol secretion. However, the widely held belief that hormonal responses are due to its 5-HT releasing action is difficult to reconcile with the persistence (sometimes increase) of responses after administration of drugs which block 5-HT reuptake, such as clomipramine, imipramine, amitriptyline, fluoxetine and fluvoxamine.29-32 Hormonal responses to fenfluramine may therefore be due to either 5-HT release independent of active 5-HT reuptake or due to direct postsynaptic receptor stimulation. Whatever the precise mechanism, antagonist studies suggest that the PRL response to fenfluramine is mediated by postsynaptic 5-HT2 receptors as they are antagonized by the 5-HT2A/2C receptor antagonists, ritanserin33 and amesergide,34 but not by pindolol35 or the 5-HT3 antagonist, ondansetron.36 The cortisol response to fenfluramine tends to be less robust; it is often not reported and the 5-HT receptors involved have been less well characterized. However, clozapine, which has 5-HT2 antagonist properties, has been shown to attenuate both PRL and cortisol responses to d-fenfluramine in schizophrenic patients.37
Clomipramine given intravenously stimulates PRL and cortisol secretion. Its metabolite, desmethylclomipramine, is a potent noradrenaline reuptake inhibitor but is not detectable during acute clomipramine challenge.38 The 5-HT receptor pathways have not been characterized as to our knowledge no antagonist studies have been carried out. Although hormonal responses are likely to be a consequence of increased synaptic 5-HT concentrations the contribution of alternative non-specific mechanisms such as a stress reaction to nausea are possible.39
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