Potentiation of 3,4-methylenedioxymethamphetamine-induced 5-HT release in the rat substantia nigra by clorgyline, a monoamine oxidase A inhibitor.
1. It is well established that the commonly used recreational drugs 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and para-methoxyamphetamine (PMA) facilitate the release and prevent the reuptake of 5-hydroxytryptamine (5-HT, serotonin). Although these drugs have similar potencies for their abilities to increase the release and inhibit the re-uptake of 5-HT, PMA has greater potency as an inhibitor of monoamine oxidase (MAO)-A. 2. The present study compared the abilities of PMA and MDMA to increase extracellular 5-HT concentrations in animals with functional MAO-A and when MAO-A activity was inhibited by clorgyline. 3. Samples of extracellular fluid from rat substantia nigra were collected using microdialysis and then analysed for 5-HT and 5-hydroxyindol acetic acid (5-HIAA) by high-performance liquid chromatography coupled with electrochemical detection. The 5-HT-mediated effects on body temperature and behaviour were also recorded. Rats were pretreated with saline or 10 mg/kg, i.p., clorgyline and, 24 h later, injected with 10 mg/kg MDMA, PMA or saline. 4. Both MDMA and PMA produced significant increases in extracellular 5-HT concentrations (482 +/- 83 and 726 +/- 287%, respectively; P < 0.05). Rats treated with PMA and MDMA displayed significantly increased 5-HT-related behavours (P < 0.05). Furthermore, only MDMA was capable of producing additional significant increases in 5-HT concentrations (1033 +/- 131%; P < 0.01) when coadministered with clorgyline. 5. The results of the present study suggest that PMA and MDMA are similar in their abilities to increase extracellular 5-HT levels in animals with functional MAO-A activity. However, coadministration of these substituted amphetamines with an MAO-A inhibitor causes significant potentiation in the ability to increase extracellular levels of 5-HT for MDMA, but not PMA.
Hewton
Ryan
R
Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
Salem
Abdallah
A
Irvine
Rodney J
RJ
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003010:Clorgyline / Q000494:pharmacology*; D004563:Electrochemistry; D004567:Electrodes, Implanted; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D000662:Amphetamines; D008996:Monoamine Oxidase Inhibitors; D018490:Serotonin Agents; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003010:Clorgyline; C100230:4-methoxyamphetamine