N, N-dimethyl- α-[2-( p-topoloxy) ethyl]benzylamine hydrochloride (LY125180) : Effects on serotonin uptake and serotonin synthesis in rat brain in vitro and in vivo

Abstract

N, N-Dimethyl- α-[2-( p-tolyloxy)ethyl]benzylamine hydrochloride (LY125180) competitively inhibited the uptake of serotonin and norepinephrine by cortical synaptosomes and of dopamine by striatal synaptosomes, with K i values of 0.06, 2.2 and 2.5 μM respectively. In platelets of human plasma, LY125180 blocked serotonin uptake by 50 per cent at 22 nM. The administration of LY125180 led to a reduction of serotonin uptake by rat hypothalamic synaptosomes with an ed 50 value of 12 mg/kg, i.p., and a maximum effect within 1 hr. Prior treatment with β-diethylaminoethyl-2, 2-diphenylvalerate, HCl (SKF-525A), an inhibitor of microsomal metabolism, enhanced the potency of LY125180 by 3-fold and prolonged its action for at least 4 hr. LY125180 in vivo blocked the neurotoxic effect of p-chloroamphetamine on serotonin uptake by cortical synaptosomes but did not prevent the neurotoxic effect of 6-hydroxydopamine on norepinephrine uptake by hypothalamic synaptosomes or the accumulation of radiolabeled norepinephrine in rat heart at 50 mg/kg, i.p. A reduction in brain level of 5-hydroxyindoleacetic acid but not of serotonin and tryptophan and a decrease in the conversion of [ 3H]tryptophan to [ 3H]serotonin and [ 3H]-5-hydroxyindoleacetic acid after the administration of LY125180 suggest a decrease of serotonin turnover in rat brain. These data are consistent with the conclusion that LY125180 is effective and selective in the blockade of the serotonin pump in vitro as well as in vivo. Except for a much shorter duration of action in vivo, LY125180 exhibits properties similar to the earlier reported selective serotonin uptake inhibitor, fluoxetine.