D-fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates

In order to test the hypothesis that the anorectic effects of D-fenfluramine involve mediation by increased serotonin (5-HT) activity we examined the effects of acute and chronic D-fenfluramine on the hypothalamic activities of 5-HT as well as the other major monoamine neurotransmitters noradrenaline (NA) and dopamine (DA). Precise and specific gas chromatograph/mass spectrometer analyses of NA, 5-HT and DA and their primary metabolites dihydroxphenylethyleneglycol (DHPG), 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC), respectively, were made in combination with analysis of the hormonal correlates of the monoamines, glucose and adrenocorticotropin for NA, thyroid-stimulating hormone for 5-HT and prolactin for DA. Acute D-fenfluramine increased NA, while reducing 5-HT, functional activity. Chronic and acute after chronic, D-fenfluramine decreased both NA and 5-HT functional activity. The effect of acute D-fenfluramine on the DA system is consistent with a post-synaptic blockade which is compensated for by chronic treatment. Since chronic D-fenfluramine acted to depress noradrenergic tone, a further study was undertaken which showed that chronic D-fenfluramine does not impair the ability noradrenergic/sympathetic system to respond to stress. The results indicate that D-fenfluramine may not exert its anorectic and weight loss effects via serotonergic agonism and involvement of the NA and/or DA systems is likely.