The vesicular monoamine transporter-2 is the sole transporter responsible f
or sequestration of monoamines, including dopamine (DA), into synaptic vesi
cles. Previous studies demonstrate that agents that inhibit DA transporter
function, such as cocaine, increase vesicular [H-3]DA uptake and binding of
the ligand [H-3]dihydrotetrabenazine ([H-3]DHTBZ), as assessed in vesicles
prepared from treated rats. The present studies examine the role of DA rec
eptors in these cocaine-induced effects. Results demonstrate that administr
ation of the D-2 DA receptor antagonist, eticlopride, but not the D-1 DA re
ceptor antagonist, SCH23390, inhibited these cocaine-induced increases. Sim
ilar to the effects of cocaine, treatment with the D-2 agonist, quinpirole,
increased both vesicular [H-3]DA uptake and [H-3]DHTBZ binding. In contras
t, administration of the D-1 agonist, SKF81297, was without effect on vesic
ular [H-3]DA uptake or [H-3]DHTBZ binding. Finally, coadministration of qui
npirole and cocaine did not further increase vesicular [H-3]DA uptake or [H
-3]DHTBZ binding when compared with treatment with either agent alone. Thes
e data suggest that cocaine-induced increases in vesicular DA uptake and DH
TBZ binding are mediated by a D-2 receptor-mediated pathway. Furthermore, r
esults indicate that D-2 receptor activation, per se, is sufficient to incr
ease vesicular DA uptake.