Kinetic evaluation of the commonality between the site(s) of action of cocaine and some other structurally similar and dissimilar inhibitors of the striatal transporter for dopamine.
The inhibition by cocaine of the apparent initial rate of the transport of striatal dopamine was compared with inhibitions produced by cocaethylene, benztropine, GBR-12909, mazindol, and nomifensine. Rotating disk electrode voltammetry was used to measure the kinetically resolved, inwardly directed transport of dopamine in striatal suspensions. Evidence is presented that the primary site of action of cocaine may be at the external face of the transporter. Experiments to determine whether or not the other inhibitors bind to the same site as cocaine were conducted by comparing the inhibitions observed for each of the inhibitors alone with that observed when paired with cocaine. The resulting changes in the velocity of the transport of dopamine induced by the inhibitors were then fit to one of the previously developed models of inhibition by pairs of inhibitors affecting the kinetics of actively transporting systems: a single-site model, a two-site model in which the two binding sites for the inhibitors interact, and a two-site model in which the two binding sites for the two inhibitors act independently. Cocaine inhibited the transport of dopamine competitively with its structural analogues, cocaethylene and benztropine. The structurally dissimilar inhibitor, GBR-12909, was found also to be competitive with cocaine. In contrast, mazindol and nomifensine were found to bind to separate interactive sites when individually paired with cocaine. These results suggest that mazindol and nomifensine may interact with the kinetically active transporter for dopamine in a manner different from that of cocaine. Mazindol was tested and found to inhibit competitively the inward transport of dopamine into striatal suspensions. In contrast, our previous published findings show cocaine to be an uncompetitive inhibitor of the transport of striatal dopamine. These results suggest that cocaine inhibits inward transport of dopamine by reducing the intramembrane turnover of the transporter, whereas mazindol alters the kinetics of the recognition of dopamine by the transporter. Finally, the potential effects of these binding modes of inhibitors on synaptic chemical communication in dopaminergic systems were analyzed. The results of these analyses suggest that different effects on the extracellular concentrations of dopamine can result from the different patterns of inhibition, suggesting that different modulatory influences on pre- and postsynaptic receptor occupation can result from inhibition of the transport of dopamine.
Meiergerd
S M
SM
Department of Chemistry, Washington State University, Pullman 99164-4630.
Schenk
J O
JO
D000818:Animals; D001590:Benztropine / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008454:Mazindol / Q000494:pharmacology; D008954:Models, Biological; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009627:Nomifensine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D009627:Nomifensine; D001590:Benztropine; C043425:vanoxerine; D008454:Mazindol; C066444:cocaethylene; D003042:Cocaine; D004298:Dopamine