Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on 5-HT cell firing and release: comparison between dorsal and median raphe 5-HT systems.
It is proposed that 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) is more toxic to 5-HT neurones projecting from the dorsal raphe nucleus (DRN) than to those from the median raphe nucleus (MRN). Since increased 5-HT release has been associated with MDMA-induced neurotoxicity, MDMA may have a DRN-selective 5-HT releasing effect. Here we have compared the effects of acute MDMA on DRN and MRN 5-HT pathways using in vivo electrophysiological and neurochemical techniques. MDMA inhibited the firing of 5-HT neurones in both the DRN and the MRN, and did so with similar potency (ED50 values, 0.589 +/- 0.151 (8) and 0.588 +/- 0.207 (6) mg/kg i.v., respectively). In both nuclei this inhibitory effect was reversed by the selective 5-HT1A receptor antagonist, WAY 100635 (0.1 mg/kg i.v.). Microdialysis measurements were made in the frontal cortex and dorsal hippocampus, regions which receive a DRN- and an MRN-selective 5-HT innervation, respectively. A dose of 1 mg/kg i.v. MDMA increased extracellular 5-HT 3-fold in both the frontal cortex and dorsal hippocampus. A higher dose (3 mg/kg i.v.) increased 5-HT levels 8-fold in both regions. Overall, our data suggest that MDMA releases 5-HT from the cell body and terminal regions of both DRN and MRN 5-HT pathways, and does so in a qualitatively and quantitatively similar fashion. We conclude that any DRN-selectivity in the neurotoxic effects of MDMA is not due to a DRN-selective, acute 5-HT releasing action of the drug.
Gartside
S E
SE
University of Oxford Department of Clinical Pharmacology, Radcliffe Infirmary, UK.
McQuade
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R
Sharp
T
T
D002851:Chromatography, High Pressure Liquid; D004558:Electric Stimulation; D004563:Electrochemistry; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013238:Stereotaxic Techniques
D010879:Piperazines; D011725:Pyridines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D018817:N-Methyl-3,4-methylenedioxyamphetamine