Fluoro-gold and pentamidine inhibit the in vitro and in vivo release of dopamine in the striatum of rat.
Fluoro-Gold (FG), first developed as an antifungal/antiparasitic agent, is now also used extensively as a retrograde tracer in histological studies of nervous tissue. The fact that FG is taken up by dopamine (DA) terminals before its retrograde transport to DA cell bodies implies a presynaptic interaction, though the biochemical target(s) and mechanism(s) are unknown. To further elucidate, FG and another aromatic diamidine, pentamidine, were tested on [3H]DA release and uptake in vitro from striatal slices and synaptosomes. Neither compound affected [3H]DA uptake in synaptosomes and slices, and neither inhibited DA efflux mediated through reversal of DA uptake mechanisms. NMDA-mediated glutamate-evoked DA release was completely inhibited by either FG (IC50 approximately 3 microM) or pentamidine (IC50 approximately 1 microM), and 20 mM K(+)-evoked DA release was inhibited by similar concentrations but only to 60% of control. Arginine (up to 500 microM) and spermidine (200 microM) failed to reverse 33 microM FG inhibition of either the spontaneous or the glutamate-evoked DA release, indicating that FG inhibition of release was not necessarily via blockade of either nitric oxide generation or spermidine binding to NMDA receptors. Interestingly, FG (33 microM) and pentamidine (10 microM) inhibited 1 and 5 microM D-methamphetamine (METH)-evoked [3H]DA release to approximately 50% of control, and in striatal synaptosomes, FG (33 microM) and pentamidine (10 microM) inhibited 5 microM METH- and 1.25 mM Ca(++)-evoked DA release. Additionally, in vivo brain microdialysis supported the in vitro results; 100 microM FG in the microdialysis buffer inhibited 70% of the increase in extracellular DA in the striatum produced by 2.5 mg/kg METH.(ABSTRACT TRUNCATED AT 250 WORDS)
Bowyer
J F
JF
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Gough
B
B
Broening
H W
HW
Newport
G D
GD
Schmued
L
L
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D010419:Pentamidine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013266:Stilbamidines
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005456:Fluorescent Dyes; D013266:Stilbamidines; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D010419:Pentamidine; D012110:Reserpine; D011188:Potassium; D004298:Dopamine