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Comparative effects of substituted amphetamines (PMA, MDMA, and METH) on monoamines in rat caudate: a microdialysis
Bobby Gough1, Syed Z Imam, Bruce Blough
1Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, Arkansas 72079, USA.
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.
Insights
Paramethoxyamphetamine (PMA) and MDMA cause neurotoxicity by affecting dopamine and serotonin levels in rats. This study compares the neurotoxic effects of PMA, MDMA, and METH, revealing significant impacts on neurotransmitter systems.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Paramethoxyamphetamine (PMA) is an illicitly used phenethylamine derivative.
- PMA has been linked to fatalities when misrepresented as MDMA (ecstasy).
- Understanding the neurotoxic potential of PMA is crucial due to its increasing illicit use.
Purpose of the Study:
- To evaluate and compare the neurotoxicity of substituted amphetamines, specifically PMA, MDMA, and METH.
- To investigate the effects of these substances on key neurotransmitter levels in the rat brain.
Main Methods:
- Rats were administered intraperitoneal injections of PMA, MDMA, or METH at varying doses.
- Extracellular levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT), and 5-HIAA were measured in the caudate nucleus.
- Microdialysis and High-Performance Liquid Chromatography with Electrochemical Detection (HPLC-EC) were employed for neurochemical analysis.
Main Results:
- METH and MDMA significantly increased extracellular DA and decreased DOPAC and HVA.
- MDMA also significantly increased 5-HT and decreased 5-HIAA.
- PMA showed dose-dependent effects, significantly increasing DA only at the highest dose, but consistently decreasing DOPAC, HVA, and 5-HIAA across tested doses, with 5-HT increases at higher doses.
Conclusions:
- PMA, MDMA, and METH exhibit neurotoxic potential by altering dopaminergic and serotonergic systems.
- PMA demonstrates significant neurochemical changes indicative of neurotoxicity, similar to MDMA and METH.
- These findings highlight the risks associated with PMA consumption and its potential for severe neurological damage.