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Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor

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Abstract

Paroxetine was shown to be a potent (K i =1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED 50=1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED 50>30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED 50 1–3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for α1, α2 or β adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (K i =89 nM) but was at least 15 fold weaker than amitriptyline (K i =5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.

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  1. Beecham Pharmaceuticals Research Division, Harlow, Essex, UK

    D. R. Thomas, D. R. Nelson & A. M. Johnson

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  1. D. R. Thomas
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  2. D. R. Nelson
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  3. A. M. Johnson
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Thomas, D.R., Nelson, D.R. & Johnson, A.M. Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor. Psychopharmacology 93, 193–200 (1987). https://doi.org/10.1007/BF00179933

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  • DOI: https://doi.org/10.1007/BF00179933

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