The effect of polychlorinated biphenyls on the uptake of dopamine and other neurotransmitters into rat brain synaptic vesicles.
Studies have shown that polychlorinated biphenyls may affect cognitive functions both in human and also in experimental animals. One of the neurochemical parameters that is changed after exposure to these compounds is a reduction in the dopamine level in the brain, although the mechanism behind this reduction is not known. We have therefore investigated whether this reduction could be caused by an effect on vesicular uptake. ortho-Chlorinated biphenyls are found to be competitive inhibitors of dopamine transport into synaptic vesicles from rat brain with K(i) concentrations as low as 4 microM. In contrast, several nonortho-chlorinated biphenyls did not inhibit vesicular uptake. The inhibition was specific for dopamine, in that the uptake of glutamate and GABA was inhibited at higher PCB concentrations under identical conditions. The vesicular Mg-ATPase proton pump was also inhibited at higher concentrations of PCBs than the dopamine transport. Uptake of methylamine gave no indication of any disruption of the vesicular proton gradient. The inhibition of dopamine vesicular uptake by PCBs was competitive. Several of the ortho-PCBs also inhibited the binding of tetrabenazine, which is known to bind to a site close to the dopamine binding site, at the vesicular transporter. The results show that inhibition of vesicular uptake may contribute to the decrease of dopamine reported in nervous tissue after exposure to PCBs under different conditions.
Mariussen
E
E
Norwegian Defence Research Establishment, Kjeller, 2027, Norway. espen.mariussen@ffi.no
Morch Andersen
J
J
Fonnum
F
F
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000633:toxicity; D018698:Glutamic Acid / Q000493:pharmacokinetics; D008297:Male; D008744:Methylamines / Q000493:pharmacokinetics; D015394:Molecular Structure; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism; D013747:Tetrabenazine / Q000378:metabolism / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D008744:Methylamines; D012701:Serotonin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C027451:methylamine; D011078:Polychlorinated Biphenyls; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases; D004298:Dopamine; D013747:Tetrabenazine