Abstract
Recent studies identified novel allosteric modulators of the dopamine (DA) transporter (DAT). N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine (SoRI-9804), N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine (SoRI-20040), and N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine (SoRI-20041) partially inhibited [(125)I]3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [(125)I]RTI-55 from the DAT, and partially inhibited [(3)H]dopamine uptake. In the present study, we report that SoRI-9804 and SoRI-20040, at doses that do not alter release, partially inhibited d-amphetamine-induced DAT-mediated release of [(3)H]1-methyl-4-phenylpyridinium (MPP(+))or[(3)H]dopamine from striatal synaptosomes ("DAT-mediated DA release") in a dose-dependent manner. SoRI-20041, which does not alter DAT-mediated DA release measured with [(3)H]DA, reversed the effect of SoRI-20040. SoRI-20040 and SoRI-9804 also partially inhibited DAT-mediated DA release induced by DA or (+/-)-3,4-methylenedioxyamphetamine, demonstrating that the observed partial inhibition is not specific for a particular DAT substrate. SoRI-9804 and SoRI-20040 did not attenuate D-amphetamine-induced release of [(3)H]5-hydroxytryptamine from serotonergic, or [(3)H]MPP(+) from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of [(3)H]MPP(+) from dopaminergic nerve terminals without altering the apparent rate constants. The two major findings of this study are 1) the identification of both "agonist" (SoRI-9804 and SoRI-20040) and "antagonist" (SoRI-20041) allosteric modulators of D-amphetamine-induced DAT-mediated DA release and 2) [(3)H]DA uptake and d-amphetamine-induced DAT-mediated efflux can be separately modulated. Such agents may have therapeutic potential for the treatment of stimulant addiction, Parkinson's disease, and other psychiatric disorders.