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.