Effect of long term amineptine treatment on pre‐ and postsynaptic mechanisms in rat brain

Abstract

1 The effect of amineptine and its two metabolites on monoamine uptake, release and receptor binding was studied in vitro. 2 Amineptine and its two metabolities did not displace labelled ligands for known neurotransmitters and drug receptor sites. 3 Amineptine and its two metabolities did not influence [³H]-5-hydroxytryptamine ([³H]-5-HT) uptake or release by rat brain synaptosomes. Amineptine inhibited [³H]-dopamine and [³H]-noradrenaline ([³H]-NA) accumulation, with IC₅₀ values of 1.4 and 10 μM, respectively. The effect was retained, though with lower efficacy, by the two metabolites. 4 Amineptine released [³H]-dopamine from preloaded synaptosomes. Metabolite 1 had no effect on catecholamine release, and metabolite 2 was about half as active as the parent compound on [³H]-dopamine release. 5 The releasing effect of amineptine on [³H]-dopamine was potentiated by reserpine pretreatment, suggesting that the drug acts on the cytoplasmic neurotransmitter pool. 6 Chronic treatment with amineptine (20 mg kg⁻¹, twice daily for 15 days followed by a 3 days drug withdrawal period) resulted in a decrease of [³H]-spiperone binding sites in striatum, and of [³H]-dihyroalprenolol and [³H]-clonidine in cortex. 7 Chronic treatment with amineptine reduced basal [³H]-dopamine accumulation in striatal synaptosomes, without affecting [³H]-NA or [³H]-5-HT accumulation. 8 The adaptive changes in the pre- and postsynaptic dopamine mechanisms observed after long term treatment with amineptine are consistent with the drug acting as an indirect dopamine agonist. 9 The down regulation of β- and α₂-noradrenoceptors observed after long term amineptine treatment may play a role in the antidepressant activity of the drug.