Abstract
The anorexigenic drug d-fenfluramine (d-F) increased the in vitro release of [3H]5-hydroxytryptamine ([3H]-5-HT) from rat hypothalamic synaptosomes. The release induced by 5 microM d-F was Ca(++)-independent, insensitive to 5-HT autoreceptor activation and prevented by the 5-HT uptake inhibitor fluoxetine (0.1 microM). The release evoked by 0.5 microM d-F also was blocked by fluoxetine, but it was Ca(++)-dependent and sensitive to autoreceptor activation. Thus, relatively high concentrations of d-F release 5-HT through an outward carrier mediated transport; at 0.5 microM the evoked release seems instead exocytotic, although it probably requires previous uptake of d-F by the 5-HT transporter. During in vivo intrahypothalamus microdialysis, in free-moving rats, local infusion (0.5 or 5 microM) or i.p. administration (0.8 or 2.5 mg/kg) of d-F produced increases of extracellular 5-HT. These effects were prevented completely by local (0.1 microM) or i.p. (1 mg/kg) administration of fluoxetine. Although both 0.8 and 2.5 mg/kg of d-F consistently increased hypothalamic extracellular 5-HT, only the higher dose induced hypophagia. This hypophagia was, however, not significantly modified by fluoxetine, although it was blocked by the 5-HT receptor antagonist metergoline (2 mg/kg i.p.). The results show that d-F is a potent 5-HT releaser also in the hypothalamus, one major site of action of the anorexigenic drug. Depending on the concentration, the release elicited by d-F may occur by a dual mechanism requiring integrity of the 5-HT transporter.(ABSTRACT TRUNCATED AT 250 WORDS)
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