Significant progress was made during this reporting period. We continued to evaluate a large number of newly synthesized compounds were evaluated using in vitro assays. Several papers were also published during the reporting period. Two will be highlighted here. Paper #1 (Studies of the biogenic amine transporters. 13. Identification of agonist and antagonist allosteric modulators of amphetamine-induced dopamine release. J Pharmacol Exp Ther 329:718-28): """"""""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)I3beta-(4'-iodophenyl)tropan-2beta-carboxylic acid methyl ester (RTI-55) binding, slowed the dissociation rate of (125)IRTI-55 from the DAT, and partially inhibited (3)Hdopamine 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)H1-methyl-4-phenylpyridinium (MPP(+))or(3)Hdopamine 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)HDA, 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)H5-hydroxytryptamine from serotonergic, or (3)HMPP(+) from noradrenergic, nerve terminals. Kinetic experiments demonstrated that SoRI-9804, in contrast to cocaine, slowed D-amphetamine-induced release of (3)HMPP(+) 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)HDA 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."""""""" Paper #2 (Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. J Pharmacol Exp Ther 329:738-46 ): """"""""Modafinil is prescribed for numerous medical conditions, but the drug's mechanism of action is unclear. Here, we examined the interaction of modafinil with receptors and transporters in vitro and compared pharmacological effects of the drug with those produced by indirect dopamine (DA) agonists 1-2-bis(4-fluorophenyl)methoxyethyl-4-(3-phenylpropyl)piperazine (GBR12909) and (+)-methamphetamine (METH). Modafinil was screened at various receptors and transporters using binding assays. Transporter-mediated uptake and release were examined in rat brain synaptosomes. Effects of modafinil on motor activity and neurochemistry were determined in rats undergoing in vivo microdialysis in nucleus accumbens. Of the receptors and transporters assayed, modafinil displayed measurable potency only at DA transporters (DAT), inhibiting (3)HDA uptake, with an IC(50) value of 4.0 microM. Accordingly, modafinil pretreatment (10 microM) antagonized METH-induced release of the DAT substrate (3)H1-methyl-4-phenylpyridinium. Intravenous modafinil (20 and 60 mg/kg) produced dose-dependent increases in motor activity and extracellular DA, without affecting serotonin (5-HT). Analogous results were observed for GBR12909 (1 and 3 mg/kg), whereas METH (0.3 and 1 mg/kg) increased DA and 5-HT. Locomotor effects of all drugs were positively correlated with dialysate DA (P <0.001). Interestingly, modafinil pretreatment reduced METH-induced ambulation and DA release. Our data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence. Nondopaminergic mechanisms may also contribute to the pharmacology of modafinil. Finally, the results suggest that modafinil should be tested as an adjunct for treating METH addiction.""""""""
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