RT Journal Article
SR Electronic
T1 Studies of the Biogenic Amine Transporters. 13. Identification of “Agonist” and “Antagonist” Allosteric Modulators of Amphetamine-Induced Dopamine Release
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 718
OP 728
DO 10.1124/jpet.108.149088
VO 329
IS 2
A1 Rothman, Richard B.
A1 Dersch, Christina M.
A1 Ananthan, Subramaniam
A1 Partilla, John S.
YR 2009
UL http://jpet.aspetjournals.org/content/329/2/718.abstract
AB 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 [125I]3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of [125I]RTI-55 from the DAT, and partially inhibited [3H]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 [3H]1-methyl-4-phenylpyridinium (MPP+)or[3H]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 [3H]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 [3H]5-hydroxytryptamine from serotonergic, or [3H]MPP+ from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed d-amphetamine-induced release of [3H]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) [3H]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. U.S. Government work not protected by U.S. copyright