Development of a rationally-designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration
Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS,
Mello NK, Roth BL, Baumann MH. IRP, NIDA, NIH.
J Pharmacol Exp Ther. 2005 Mar 10
ABSTRACTConvergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and serotonin (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a non-amphetamine 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 CNS stimulants. In the present work, over 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT and norepinephrine (NE) transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a non-amphetamine 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 which increases only extracellular DA. Administration of high-dose (+)-methamphetamine or (+/-)-MDMA to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg, i.p. X 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/hr. Collectively, the findings reported here demonstrate that non-amphetamine monoamine releasing agents like PAL-287 might be promising candidate medications for the treatment of stimulant dependence.JHW007
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