D- and L-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

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 1-fenfluramin 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 1-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 1-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 1- 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 1-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. The effect of d-fenfluramine on brain 5-HT seems to be important for its anorectic activity while the functional outcome of the interaction of l-fenfluramine with catecholamines remains to be clarified.