N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')

3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') is an illicit drug that stimulates the release of serotonin (5-HT) and dopamine (DA) from neurons. Recent evidence reveals that drug users are ingesting piperazine analogs, like 1-benzylpiperazine (BZP, or 'A2') and 1-(m-trifluoromethylphenyl) piperazine ( TFMPP, or 'Molly'), to mimic psychoactive effects of MDMA. In the present study, we compared the neurochemistry of MDMA, BZP, and TFMPP in rats. The effects of MDMA, BZP, and TFMPP on transporter-mediated efflux of [H-3] 5-HT and [H-3] MPP+ ( DA transporter substrate) were determined in synaptosomes. The effects of drugs on extracellular levels of 5-HT and DA were examined using in vivo microdialysis in conscious rats. MDMA evoked transporter-mediated release of [H-3] 5- HT and [H-3] MPP+. BZP released [H-3] MPP+, whereas TFMPP was a selective releaser of [H-3] 5-HT. MDMA ( 1 - 3 mg/kg, i.v.) increased dialysate 5- HT and DA in a dose-related fashion, with actions on 5- HT being predominant. BZP ( 3 - 10 mg/kg, i.v.) elevated dialysate DA and 5- HT, while TFMPP ( 3 - 10 mg/kg, i.v.) elevated 5- HT. Administration of BZP plus TFMPP at a 1: 1 ratio (BZP/TFMPP) produced parallel increases in dialysate 5- HT and DA; a 3 mg/kg dose of BZP/TFMPP mirrored the effects of MDMA. At a 10 mg/kg dose, BZP/TFMPP increased dialysate DA more than the summed effects of each drug alone, and some rats developed seizures. Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug - drug synergism may occur when piperazines are coadministered at high doses.