Abstract
The effects of prolonged treatment of rats with zimelidine, 5, 12.5, and 25 μmol/kg PO twice daily for 2 weeks, on the accumulation of 14C-5-hydroxytryptamine (14C-5-HT) and 3H-noradrenaline (3H-NA) in hypothalamic slices were studied. The concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in whole brain, the concentration of 5-HT in whole blood and the in vitro labelling of receptors in cerebral cortex with 3H-5-HT, 3H-dihydroalprenolol (3H-DHA) and striatum with 3H-spiroperidol were also determined, and the concentrations of zimelidine and its demethylated metabolite norzimelidine in plasma and hypothalamus were analysed. The degree of inhibition of the accumulation of 14C-5-HT and 3H-NA was not changed or only slightly increased by prolonged treatment as compared to acute treatment with zimelidine, i.e. the 5-HT accumulation was more inhibited than the NA accumulation. The inhibition of 14C-5-HT accumulation was significantly correlated to the plasma and hypothalamic concentration of norzimelidine 14 h after the last repeated administration. The 5-HT concentration in whole blood was markedly reduced at the same doses which produced inhibition of 5-HT uptake in brain, which indicates that the inhibition of 5-HT uptake in platelets and in neurons are similarly affected. The concentration of 5-HIAA in whole brain was reduced by both single and repeated administration of zimelidine, whereas the concentration of 5-HT was decreased only after prolonged treatment. The density of β-adrenoceptors (binding of 3H-DHA) was significantly reduced by zimelidine, whereas 5-HT receptor binding (3H-5-HT) and dopamine receptor binding (3H-spiroperidol) were unchanged. It is concluded that the effects on 5-HIAA and 5-HT levels in brain and on the β-adrenoceptors in cerebral cortex reflect pre-and post-synaptic regulation resulting from the uptake inhibition.
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Ross, S.B., Hall, H., Renyi, A.L. et al. Effects of zimelidine on serotoninergic and noradrenergic neurons after repeated administration in the rat. Psychopharmacology 72, 219–225 (1981). https://doi.org/10.1007/BF00431820
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DOI: https://doi.org/10.1007/BF00431820