title: Persistent cerebrovascular effects of MDMA and acute responses to the drug.
abstract: Acutely, 3,4,-methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [Quate et al., (2004)Psychopharmacol., 173, 287-295]. In the longer term the same single dose results in depletion of 5-hydroxytrptamine (5-HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre-treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre-treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [(14)C]-iodoantipyrine and [(14)C]-2-deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [(3)H]-paroxetine and immunohistochemistry. Three weeks after MDMA pre-treatment there were significant reductions in densities of 5-HT transporter (SERT)-positive fibres (-46%) and [(3)H]-paroxetine binding (-47%). In animals pre-treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre-treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA-pre-treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA-induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5-HT terminals. However, there may be a sub-population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.
authors.affiliation: Division of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK. linda.ferrington@ed.ac.uk
authors.forename: Linda
authors.initials: L
authors.lastname: Ferrington
authors.forename: Eszter
authors.initials: E
authors.lastname: Kirilly
authors.forename: Douglas E
authors.initials: DE
authors.lastname: McBean
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Olverman
authors.forename: György
authors.initials: G
authors.lastname: Bagdy
authors.forename: Paul A T
authors.initials: PA
authors.lastname: Kelly
mesh_terms: D000208:Acute Disease; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000378:metabolism; D017776:Autonomic Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002250:Carbon Radioisotopes; D002536:Cerebral Arteries / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006940:Hyperemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000009:adverse effects*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000009:adverse effects; D020521:Stroke / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013995:Time; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D002250:Carbon Radioisotopes; D018490:Serotonin Agents; D012701:Serotonin; D003847:Deoxyglucose; D005947:Glucose; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000983:Antipyrine; C008135:iodoantipyrine