Changes in dopamine metabolism in rat forebrain regions after cessation of long-term fluoxetine treatment: relationship with brain concentrations of fluoxetine and norfluoxetine.

We examined the effects of repeated administration of the selective serotonin uptake inhibitor (SSRI) fluoxetine (Flx) (5, 10, or 15 mg/kg i.p., twice daily for 21 days) on brain and plasma concentrations of the parent drug and its active desmethyl metabolite, norfluoxetine (NFlx), in rats during the 21-day regimen as well as after cessation of drug treatment. We also measured dopamine (DA) levels in 2 midbrain regions (the striatum, St and nucleus accumbens, NAc) in rats killed 1-14 days after the last dose. NFlx concentrations in plasma and brain were ten times higher than those of Flx during the period of drug treatment. Although Flx accumulated more markedly in the rat brain than NFlx, it disappeared completely from plasma and brain after treatment stopped, while NFlx persisted up to Day P7. Chronic Flx treatment caused a persistent decrease in brain DA levels of -60% to -70% in St and NAc; this lasted for 7-14 days after cessation of treatment, depending on the dose used. The levels of DA metabolites decreased by 20-40%, and, except for 3-MT, tended to overshoot during the recovery period. Our data suggest that the long-term inhibition of DA neurons after cessation of Flx treatment parallels the inhibition previously observed for 5-HT neurons. Thus, besides blocking 5-HT uptake, Flx is likely to also inhibit in vivo DA uptake in forebrain regions, following prolonged administration.