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NEUROPHARMACOLOGY

Studies of the Biogenic Amine Transporters. 13. Identification of "Agonist" and "Antagonist" Allosteric Modulators of Amphetamine-Induced Dopamine Release

Clinical Psychopharmacology Section, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R., C.M.D., J.S.P.); and Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama (S.A.)

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.

Address correspondence to: Dr. Richard B. Rothman, Clinical Psychopharmacology Section, Suite 4500, Triad Bldg., National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Dr., Baltimore, MD 21224. E-mail: rrothman{at}mail.nih.gov