SummaryThe high-affinity uptake of tritium labelled tryptophan (TRY), 5-hydroxytryptophan (5-HPT), 5-hydroxytryptamine (5-HT), noradrenaline (NE), dopamine (DA), glycine and glutamic acid into forebrain synaptosomes, and serum 5-HT concentrations were studied in mice. In vitro the rank order of potency (the concentration causing 50 percent uptake inhibition) of seven inhibitors of 5-HT uptake was paroxetine >citalopram > femoxetine >fluoxetine > alaproclate _->imipramine > zimelidine. Paroxetine was a weak inhibitor of the NE and DA uptake without any effect on the synaptosomal accumulation of TRY, 5-HTP, glycine or glutamic acid. Dose related inhibition of synaptosomal 5-HT uptake ex vivo was found one hour after intraperitoneal single dose administered paroxetine (EDs0 = 0.3 mg/kg i.p.) and 75% inhibition persisted 24 hours after 10 mg/kg i.p. (=ED100). Chronically administered paroxetine produced a slight decrement of synaptosomal NE uptake. Serum 5-HT concentrations were found dose dependently reduced during chronic paroxetine treatment. A dose level of paroxetine which reduced serum 5-HT concentrations with 50 % produced an almost complete inhibition of synaptosomal 5-HT uptake.