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 [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.
Footnotes
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This research was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.149088.
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ABBREVIATIONS: DAT, dopamine transporter; NET, norepinephrine transporter; SERT, serotonin transporter; BAT, biogenic amine transporter; 5-HT, 5-hydoxytryptamine (serotonin); SoRI-20040, N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine; SoRI-20041, N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine; SoRI-2827, [4-amino-6-[(diphenylmethyl)amino]-5-nitro-2-pyridinyl]carbamic acid ethyl ester; SoRI-9804, N-(diphenylmethyl)-2-phenyl-4-quinazolinamine; SoRI-6238, [5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamic acid ethyl ester; RTI-55, 3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester; TB-1-099, 4-(2-[bis(4-fluorophenyl)methoxy]ethyl)-1-(2-trifluoromethyl-benzyl)-piperidine; SA, specific activity; MDA, (±)-3,4-methylenedioxyamphetamine; MPP+, 1-methyl-4-phenylpyridinium; GBR12909, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; ANOVA, analysis of variance; Amph, amphetamine.
- Received November 23, 2008.
- Accepted February 23, 2009.
- U.S. Government work not protected by U.S. copyright
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