Antagonism of the Acute and Long–term Biochemical Effects of 4–Chloroamphetamine on the 5–HT Neurones in the Rat Brain by Inhibitors of the 5–Hydroxytryptamine Uptake

Abstract The effects of H 102/09 ((Z)–3–(4–bromophenyl)–N, N–dimethyl–3–(3–pyridyl)allylamine dihydrochloride) and chlorimipramine, two inhibitors of the membrane 5–hydroxytryptamine (5–HT) uptake, on the acute and long–term effects of 4–chloroamphetamine on the 5–HT neurones in rats were examined. The acute effect determined as the decrease in the brain level of 5–HT was antagonized by both compounds. The long–term effects determined as the decreases in 5–hydroxyindoles and the synaptosome accumulation of ¹⁴–C–5–HT were antagonized by a single injection of H 102/09 (20 mg/kg intraperitoneally) immediately before or shortly after the 4–chloroamphetamine administration. Chlorimipramine, 40 mg/kg intraperitoneally, had no antagonizing effect but on repeated injections of 40 mg/kg intraperitoneally before and four times with 3 hours' intervals after 4–chloroamphetamine, a partial antagonism of the longterm decrease in 5–HT was obtained. Combined with proadifen (SK & F 525 A) chlorimipramine partially antagonized the long–term effect. Two monoamine oxidase inhibitors (pheniprazine and clorgyline), pretreatment of the rats with p–chlorophenylalanine (2 × 300 mg/kg intraperitoneally) or proadifen alone (40 mg/kg intraperitoneally injected before and four times with 3 hours' interval) had no antagonistic effect on the long–term decrease in 5–HT. The accumulation of ³H–chloroamphetamine in synaptosomes of the hypothalamus midbrain region was slightly decreased by high concentrations of H 102/09 at 37° and 0°. H 102/09 decreased slightly but significantly the ratio between the ³H–chloramphetamine in the synaptosomal fraction and the supernatant as obtained when the rats were killed 2 hours after the injection. The increased efflux of ³H–5–HT from synaptosomes in vitro produced by 4–chloroamphetamine, ouabain and low external Na⁺ concentrations was in all cases inhibited by H 102/09 at 2.5 × 10^–6 M. Although the antagonism of the acute effect of 4–chloroamphetamine seems to be related to inhibition of the membrane 5–HT transport mechanism the antagonism of the long–term, irreversible effect produced by 4–chloroamphetamine may also involve an additional as yet unknown mechanism.