d-fenfluramine increases striatal extracellular dopamine in vivo independently of serotonergic terminals or dopamine uptake sites.
The effect of various doses of the serotonin (5-HT) release-inducing agent d-fenfluramine (d-fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d-fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 microM). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 microM d-fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 microM d-fenf was slightly but significantly reduced by the local application of 25 microM citalopram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 microM) did not modify significantly the effect of d-fenf. The rise of DA outflow induced by 25 microM d-fenf was strongly reduced in the presence of 1 microM tetrodotoxin (TTX) or by the removal of Ca2+ from the perfusion medium. The results obtained show that d-fenf increases the striatal extracellular DA concentration by a Ca(2+)-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.
De Deurwaerdère
P
P
Université de Bordeaux II, INSERM U. 259, Bordeaux, France.
Bonhomme
N
N
Le Moal
M
M
Spampinato
U
U
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism*; D005277:Fenfluramine / Q000008:administration & dosage / Q000494:pharmacology*; D006221:Halothane; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009627:Nomifensine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D015283:Citalopram; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D005277:Fenfluramine; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D013779:Tetrodotoxin; D006897:Hydroxyindoleacetic Acid; D006221:Halothane; D004298:Dopamine