Simultaneous effects of local dexfenfluramine application on extracellular glutamate and serotonin levels in rat frontal cortex: a reverse microdialysis study.
We examined the effects of local perfusion by reverse dialysis of various doses of dexfenfluramine (D-fen; in mM: 2.4, 12, and 24) simultaneously on serotonin (5-HT; [5-HT]ext) and glutamate (Glu; [Glu]ext) extracellular levels in the frontal cortex of awake rats. D-fen induced a dose-dependent increase in both [5-HT]ext and [Glu]ext, the latter being Ca2+ -dependent and TTX-sensitive, while the former is not. Pretreatment with either the neurotoxin p-chloroamphetamine or the 5-HT uptake blocker fluoxetine, markedly reduced the effects of D-fen on [5-HT]ext and [Glu]ext compared to controls. This indicates that intact 5-HT nerve terminals may be required for D-fen to enter into neurones to release 5-HT by reversal of the 5-HT transporter, which then increases frontocortical [Glu]ext. Pretreatment with the Glu uptake blocker, L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM), significantly reduced by 40% the effect of D-fen's on [Glu]ext suggesting that Glu uptake sites are partially involved in this effect. These results strongly suggest that intracortical application, by reverse dialysis, of a high dose of D-fen increases frontocortical [Glu]ext by a dual mechanism of action: (1) by stimulating 5-HT release (a major indirect effect) that, in turn, facilitates the release of neuronal Glu; (2) by reversal of the glutamate transporter (a minor direct effect being Ca2+ -independent and TTX-insensitive).
Rocher
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Laboratoire de Neuropharmacologie UPRES EAD 2707, Institut de Signalisation et Innovation Thérapeutique (IFR-ISIT), Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
Jacquot
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Gardier
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D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D020372:Dexfenfluramine / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology
D015306:Biogenic Monoamines; D020372:Dexfenfluramine; D018698:Glutamic Acid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013779:Tetrodotoxin