Different effects of cocaine and nomifensine on dopamine uptake in the caudate-putamen and nucleus accumbens.
The effects of cocaine and nomifensine on the uptake of dopamine have been compared in the caudate-putamen and nucleus accumbens of rat brain slices. Electrical stimulation of brain slices was used to evoke dopamine efflux and the changes in dopamine concentration in the extracellular fluid were monitored with fast-scan cyclic voltammetry with Nafion-coated, carbon-fiber electrodes. The disappearance of extracellular dopamine after the stimulation fit Michaelis-Menten kinetics in both regions. Cocaine and nomifensine were found to competitively inhibit dopamine uptake in both regions. The competitive mechanism of action was apparent in the primary data because the initial uptake rates were unchanged by low doses of inhibitor, but dopamine uptake was slowed at concentrations near the Km value. In both regions, the apparent Km value increased with higher concentrations of cocaine (0.01-60 microM) or nomifensine (0.01-30 microM) in the perfusion buffer. The apparent Km values were used to obtain inhibition constants (Ki values) for the uptake inhibitors in each region. This analysis showed that cocaine had a Ki of 0.29 microM in both regions. Nomifensine, however, had a significantly higher potency in the caudate-putamen (Ki = 0.09 microM) than in the nucleus accumbens (Ki = 0.21 microM). These results show that there are differential effects of uptake inhibitors in different brain regions, and suggest that the dopamine transporter exhibits cell-specific regulation.
Jones
S R
SR
Department of Chemistry and Curriculum in Neurobiology, University of North Carolina, Chapel Hill, USA.
Garris
P A
PA
Wightman
R M
RM
D000818:Animals; D002421:Caudate Nucleus / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009627:Nomifensine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018765:Dopamine Uptake Inhibitors; D009627:Nomifensine; D003042:Cocaine; D004298:Dopamine