Effects of amiflamine and related compounds on the accumulation of biogenic monoamines in rat brain slices in vitro and ex vivo in relation to their behavioural effects

Abstract

The inhibition of the accumulation of serotonin, noradrenaline and dopamine in rat brain (occipital cortex and striatum) slices by amiflamine and its two major metabolites FLA 788(+) and FLA 668(+) was examined and compared with that of amine releasing compounds e.g. p-chloroamphetamine (PCA) and alpha-ethyltryptamine and uptake inhibitors, e.g. alaproclate, citalopram, desipramine, fluoxetine and norzimeldine. It was found that amiflamine and FLA 788(+) inhibited the accumulation of serotonin and noradrenaline but only slightly that of dopamine in vitro and ex vivo with a mechanism similar to that of PCA and alpha-ethyltryptamine, i.e. with higher potency in reserpinized rats than in normal animals suggesting amine releasing mechanisms. Similar to alpha-ethyltryptamine and PCA, amiflamine and FLA 788(+) caused behavioural changes (serotonin syndrome) which were particularly pronounced in reserpinized rats but also observed after a second administration of amiflamine in normal rats. Upon repeated administration of amiflamine the behavioural changes disappeared which indicates a functional down-regulation of the serotonin receptors responsible for this syndrome. FLA 668(+) inhibited the accumulation of noradrenaline in vitro and ex vivo but had less effect on the accumulation of dopamine and particularly that of serotonin. It is concluded that amiflamine and FLA 788(+) inhibit the accumulation of serotonin and noradrenaline by releasing mechanisms and that the released serotonin triggers the behavioural changes observed.