DL-fenfluramine increases the 5-HT synthesis rate in the terminals while decreasing it in the cell bodies of the rat brain.
The rate of 5-HT synthesis in discreet rat brain regions was determined using the alpha-[14C]methyl-L-tryptophan autoradiographic method. DL-Fenfluramine (10 mg/kg, i.p.), given 20 min before tracer injection, decreased the rate of 5-HT synthesis in the serotonergic cell bodies (-32% in dorsal and -23% in median raphe nuclei) but increased the rate in almost all the terminal areas investigated when compared to the rate in the control (saline treated) rats. The most pronounced increase was observed in the cortex (% difference of control between +22% and +49% in auditory and parietal-sensory-motor cortex, respectively), striatum (+32% in globus pallidus; +17% median part of caudatus-putamen), superior olive (+36%), dorsal hippocampus (+33%) and ventral thalamus (+29%). Our results suggest that axon terminals respond by increasing 5-HT synthesis, after enhanced release of 5-HT from terminals induced by fenfluramine. This increase in 5-HT synthesis in the terminals probably occurs as part of the compensatory mechanisms that replenish the loss of neurotransmitter from the terminal releasible pool. At the same time our data suggests that the fenfluramine-induced release of 5-HT in the cell bodies inhibits synthesis of the 5-HT through an autoreceptor.
Mück-Seler
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Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
Diksic
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D000818:Animals; D001345:Autoradiography; D001369:Axons / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000166:cytology*; D005277:Fenfluramine / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D014364:Tryptophan / Q000378:metabolism
D005277:Fenfluramine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014364:Tryptophan