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Vol. 289, Issue 1, 266-277, April 1999
Departments of
Pharmacology (N.R.Z., G.A.L., G.A.G.) and
Psychiatry
(G.A.G.),
Neuroscience Training Program (N.R.Z., G.A.G.), and
Rocky
Mountain Center for Sensor Technology (N.R.Z., G.A.G.), University of
Colorado Health Sciences Center, Denver, Colorado
Dopamine transporter (DAT) inhibitors are expected to decrease
dopamine (DA) clearance from the extracellular space of the brain. However, mazindol and cocaine have been reported to
"anomalously" increase DA clearance rate. To better understand in
vivo DAT activity both in the absence and presence of DAT inhibitors,
clearance of exogenously applied DA was measured in dorsal striata of
urethane-anesthetized rats using high-speed chronoamperometry. As
higher amounts of DA were ejected, DA signal amplitudes, but not time
courses, increased. Clearance rates increased until near maximal rates
of 0.3 to 0.5 µM/s were attained. Provided baseline clearance rates
were relatively low (< 0.1 µM/s), local application of either
nomifensine or cocaine markedly increased exogenous DA signal
amplitudes and time courses. Relative to the low baseline group,
locally applied nomifensine decreased clearance rate when baseline
clearance was high (~0.4 µM/s). However, even when baseline
clearance rates were high, systemic injection of nomifensine, mazindol,
GBR 12909, or benztropine increased DA signal amplitudes to a greater
extent than time courses, consistent with the observed increases in
clearance rates. In contrast, despite low baseline clearance rates,
systemic injection of cocaine, WIN 35,428, or
d-amphetamine preferentially increased DA signal time
course, consistent with the observed decreases in clearance rates. Our
results emphasize that as extracellular DA concentrations increase, DAT
velocity increases to a maximum, partially explaining the ability of
DAT inhibitors to increase DA clearance rates. However, by itself,
kinetic activation is not sufficient to explain the ability of certain
systemically administered DAT inhibitors to anomalously increase DA clearance.
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