N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')
Baumann MH, Clark RD, Budzynski AG,
Partilla JS, Blough BE, Rothman RB.
Clinical Psychopharmacology Section,
Intramural Research Program,
National Institute on Drug Abuse,
National Institutes of Health,
Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2005 Mar;30(3):550-60.


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 [3H]5-HT and [3H]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 [3H]5-HT and [3H]MPP+. BZP released [3H]MPP+, whereas TFMPP was a selective releaser of [3H]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.
Piperazine-like compounds/designer drugs
Antidepressant properties of BZP (Trelibet)
Screening for piperazine- and amphetamine-derived designer drugs
MDMA (Ecstasy)-like behavioural effects of N-substituted piperazines
Is BZP neuroprotective against MDMA/Ecstasy-induced neurotoxicity?
Chronic BZP exposure produces behavioural sensitization to methamphetamine

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