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Cibles sérotoninergiques et non sérotoninergiques des ISRS : approches pharmacologique et génétique in vivo chez la souris

Abstract : Selective serotonin (5-HT) reuptake inhibitors (SSRIs) directly block the 5-HT transporter(SERT) and indirectly stimulate multiple 5-HT (auto- and hetero-) receptors by enhancing itsextracellular levels in the synaptic cleft, although the role of particular receptors as well asinteraction(s) among different receptors in the therapeutic effects of SSRIs is not fullyunderstood. We tried to highlight it using neurochemical (in vivo intracerebral microdialysis) andelectrophysiological tests with a pharmacological (using escitalopram, 5-HT1A/2A receptorsagonists and antagonists) and genetic (using SERT, 5-HT1A ou 5-HT2A receptor knock-out [KO]mice) approaches. Neurochemical and electrophysiological experiments indicated that 5-HT1Aauto- and 5-HT2A hetero-receptors act in concert to maintain an inhibitory influence on theserotonergic system, particularly in response of escitalopram to increased levels of endogenous 5-HT: the absence of one receptor being compensated by an up-regulation of the other. Finally,SERT knockout mice might be a new model to test the mechanism of escitalopram for anincrease of norephedrine (NE) level.
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Thanh Hai Nguyen. Cibles sérotoninergiques et non sérotoninergiques des ISRS : approches pharmacologique et génétique in vivo chez la souris. Médecine humaine et pathologie. Université Paris Sud - Paris XI, 2011. Français. ⟨NNT : 2011PA114833⟩. ⟨tel-00663312⟩

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