Effect of D-fenfluramine on serotonin release in brains of anaesthetized rats.
Using in vivo microdialysis of brains of anaesthetized rats, we have examined the acute and chronic effects of D-fenfluramine on the release of serotonin (5-HT) and 5-HIAA within the frontal cortex, the lateral hypothalamus and the nucleus accumbens. A single dose of the drug (10 mg/kg) stimulated 5-HT release by 331-810% and decreased 5-hydroxyindoleacetic acid (5-HIAA) release by 30%, within all 3 brain areas. These changes were maximal 30 min after drug administration, and values returned to baseline after 120 min. Among animals receiving D-fenfluramine (3 or 10 mg/kg, i.p.) daily for 8 days and examined 24 h after the last dose, the basal release of 5-HT from frontal cortex was unaffected. However, the levels of 5-HT in this region, and its evoked release after a subsequent dose of D-fenfluramine (10 mg/kg), were significantly reduced in animals that had received the larger chronic dose. 5-HT release was restored to normal if such rats were given tryptophan (100 mg/kg, i.p.) 1 h prior to the acute D-fenfluramine dose; moreover, 5-HT release from, and levels in, frontal cortex also returned to normal without additional treatment after a 28-day washout period. These observations suggest that the chronic administration of D-fenfluramine fails to affect spontaneous 5-HT release in rat brain, and reduces the release evoked by acute D-fenfluramine only when very high doses are given. Moreover, this reduction is reversible with time or with administration of 5-HT's circulating precursor, tryptophan.
Laferrere
B
B
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.
Wurtman
R J
RJ
D000758:Anesthesia; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005277:Fenfluramine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000494:pharmacology
D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan