Paroxetine, a potent selective long-acting inhibitor of synaptosomal 5-HT uptake in mice

Abstract

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.

Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor

“…These data are broadly in agreement with the findings of Hyttel (1982), Claassen (1983) and Wong et al (1983). Magnusson et al (1982) have previously shown that paroxetine potently and selectively inhibits [3H]-5-HT uptake in mouse brain after intraperitoneal administration. It has now been demonstrated that using a similar ex vivo technique in rats, paroxetine is a potent inhibitor of [3H]-5-HT uptake into hypothalamic synaptosomes after oral administration (EDso = 1.9 mg/kg PO).…”

“…The selectivity of paroxetine for inhibition of [3H]-5-HT uptake in vitro and ex vivo has been shown previously using mouse brain synaptosomes (Magnusson et al 1982). Some of the data reported here have been presented previously in preliminary form (Nelson etal.…”

“…[] H20 control; [] paroxetine alone; • PCA alone; [] paroxetine + PCA ment with Magnusson et al (1982) who used mouse forebrain synaptosomes. Lineweaver-Burk and Eadie-Hofstee kinetic analysis shows that the inhibition of [3H]-5-HT uptake into rat brain hypothalamic and cortical synaptosomes by paroxetine is competitive in nature.…”

“…In the mouse, Magnusson et al (1982) showed that paroxetine produced a weak inhibition of [3H]-/-NA uptake ex vivo after repeat administration for 21 days (10 mg/kg/ day IP). The lack of effect on NA uptake seen in the present study is probably explained by the lower dose and different route of administration used.…”

Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with [ 11 C]McN 5652

“…Given a paroxetine plasma free fraction of 5% (Hyttel 1994), a plasma concentration of 2.9€0.7 ng/ ml would correspond to an intracerebral free paroxetine concentration of 0.38 nM. This value is in close agreement with published in vitro paroxetine K d values for SERT in human brain (0.15 nM; Laruelle et al 1988), and in rodent brain (0.4 nM; Magnussen et al 1982). This conclusion contrasts with the conclusions of Meyer et al (2001), who noted that SERT occupancy observed with PET was lower than predicted based on the in vitro K d of paroxetine.…”