Abstract
Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1–3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (+)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (+)-methamphetamine or (±)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. × 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.
Footnotes
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This research was supported in part by P01-DA14528 (to N.K.M.), R01-DA02519 (to N.K.M.), and K05-DA00101 (to N.K.M.) from the National Institute on Drug Abuse, National Institutes of Health. The self-administration study was supported by National Institute on Drug Abuse Grant R01 DA-10352 (to W.L.W.). W.L.W. is the recipient of National Institute on Drug Abuse Senior Scientist Award K05-DA15343. B.E.B. was supported by National Institute on Drug Abuse Grant R01 DA12970. R.B.R. and M.H.B. were supported by the Intramural Research Program, 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.104.082503.
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ABBREVIATIONS: DA, dopamine; 5-HT, 5-hydroxytryptamine (serotonin); PAL-287, 1-napthyl-2-aminopropane; NE, norepinephrine; RTI-229, 3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; HPLC, high-performance liquid chromatography; ECD, electrochemical detection; (±)-MDMA, (±)-3,4-methylenedioxymethamphetamine; FR, fixed ratio; VR, variable ratio; ANOVA, analysis of variance; DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; PPH, primary pulmonary hypertension; mCPP, m-chlorophenylpiperazine.
- Received December 20, 2004.
- Accepted February 7, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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