title: d- and l-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat.
abstract: Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than l-fenfluramine in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of l-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration l-fenfluramine 5-20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO4 levels. Neither l- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg l-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors; D002395:Catecholamines / Q000378:metabolism*; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D008711:Metergoline / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D002395:Catecholamines; D008711:Metergoline; D005277:Fenfluramine; D012701:Serotonin; D006916:5-Hydroxytryptophan; D002262:Carboxy-Lyases