Comparative Effects of Substituted Amphetamines (PMA, MDMA, and METH) on Monoamines in Rat Caudate

Abstract

Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has been used illicitly in Australia since 1994. PMA is also becoming popular at rave parties in the United States. PMA raised concern when a series of fatalities resulted after its use in South Australia, where it was marketed as “ecstasy,” which is the colloquial name for MDMA. In the present study, we evaluated the comparative neurotoxicity of substituted amphetamines in rats. Extracellular levels of dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) were assayed in the caudate of freely moving rats using microdialysis and HPLC‐EC. Dialysates were assayed every 20 minutes for 4 hours after an intraperitoneal (i.p.) injection of PMA (2.5, 5, 10, 20 mg/kg), MDMA (10 and 20 mg/kg), or METH (2.5 mg/kg). METH produced a significant increase in extracellular DA (700%), and significant decreases in extracellular DOPAC and HVA (30% and 50%), with no detectable changes in either 5‐HT or 5‐HIAA. MDMA produced significant increases in DA (700% at 10 mg/kg and 950% at 20 mg/kg) and decreases in DOPAC (15% for both 10 and 20 mg/kg), and HVA (50% at 10 mg/kg and 35% at 20 mg/kg). MDMA also increased 5‐HT (350% at 10, and 575% at 20 mg/kg), and decreased 5‐HIAA to 60% for both dose levels. PMA produced no detectable increases in DA at dose levels of 2.5, 5, or 10 mg/kg, but significantly increased DA (975%) at a dose of 20 mg/kg. However, PMA significantly decreased DOPAC at all dose levels (75% at 2.5; 40% at 5; 30% at 10; 10% at 20 mg/kg), with comparable decreases in HVA at all dose levels. PMA also produced significant increases in 5‐HT at 10 and 20 mg/kg (350% for both dose levels), with no detectable changes in 5‐HT at 2.5 or 5 mg/kg. All dose levels of PMA significantly decreased 5‐HIAA (50 to 70%). These data suggest that PMA, like MDMA and METH, is capable of producing dopaminergic and serotonergic neurotoxicity.

Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

“…When the dose of MDMA was increased to 7.5 mg/kg ip, extracellular levels of 5-HT and DA increased to 30-fold and 5-fold above baseline, respectively. Many investigators have demonstrated that high-dose MDMA increases dialysate levels of 5-HT and DA in diverse brain regions (Gudelsky and Nash, 1996, Kankaanpaa et al, 1998, Gough et al, 2002. The in vivo microdialysis data are consistent with the established molecular mechanism of MDMA which involves transporter-mediated release of monoamines from neurons (White et al, 1996, Rothman and Baumann, 2002, Green et al, 2003.…”

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

“…However, the ED 50 value of norZTP required for inhibition of MAP-induced hyperlocomotion was actually comparable with that of ZTP. Because MAP increases concentrations of several neurotransmitters in extracellular fluid (Gough et al, 2002), antagonisms of 5-HT and H 1 receptors and a number of other mechanisms have been suggested to be involved in the inhibitory activities of antipsychotics on such MAP-induced behaviors. As such, the present findings suggestive of norZTP's D 2 -blocking activity do not fully explain the inhibitory activity of norZTP on MAP hyperlocomotion, indicating that other mechanisms may be involved in this activity.…”

Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

“…Further, it prevents 5-HT reuptake (Iravani et al, 2000) and inhibits the activity of the catabolytic enzyme monoamine oxidase A (Leonardi and Azmitia, 1994). Concomitant elevations in dopamine (DA) and noradrenaline (NA) levels occur either via a similar pattern of direct actions upon catecholaminergic pathways (Gough et al, 2002;Baumann et al, 2005Baumann et al, , 2008 and/or events downstream of serotonergic transmission, such as activation of 5-HT 2A receptors (Gobert et al, 2000). Moreover, at high concentrations, MDMA binds to 5-HT 2A , histamine H 1 , and muscarinic M 1 /M 2 receptors, though their putative roles in its functional actions remain poorly characterized (Green et al, 2003).…”