THE EFFECTS OF SINGLE AND REPEATED ANORECTIC DOSES OF 5-HYDROXYTRYPTAMINE UPTAKE INHIBITORS ON INDOLE LEVELS IN RAT-BRAIN

1 The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on t he content of brain indoles were compared in rats in relation to the b rain regional concentrations of unchanged drug and its known active me tabolite. 2 Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertr aline significantly enhanced the content of 5-HT in the cortex. 3 The regional sensitivity to the acute effect of a given drug was not relat ed to any preferential drug distribution, as these compounds distribut ed almost uniformly in the brain areas considered (cortex, striatum an d hippocampus). 4 Repeating the same doses twice daily, i.p. for 14 da ys, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertra line lowering both 5-HT and 5-HIAA in all the brain regions compared t o pair-fed control animals, 1 h after the last dose. 5 One week later only fluoxetine-treated animals still had reduced brain 5-HT, this pro bably being related to the accumulation of its main metabolite norfluo xetine in rat brain after chronic dosing. 6 Further studies on the rel ationship between the long-term neurochemical changes and anorectic ac tivity are required but it appears from these results that anorectic d rugs with similar acute effects on 5-HT uptake may differ in their lon g-term effects on 5-HT mechanisms.