title: Investigation of the mechanisms mediating MDMA "Ecstasy"-induced increases in cerebro-cortical perfusion determined by btASL MRI.
abstract: BACKGROUND
  Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI.
  
  
  OBJECTIVE
  The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats.
  
  
  METHODS
  Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI.
  
  
  RESULTS
  Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion.
  
  
  CONCLUSIONS
  Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion.
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College, Dublin, 2, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Rouine
authors.forename: M E
authors.initials: ME
authors.lastname: Kelly
authors.forename: C
authors.initials: C
authors.lastname: Jennings-Murphy
authors.forename: P
authors.initials: P
authors.lastname: Duffy
authors.forename: I
authors.initials: I
authors.lastname: Gorman
authors.forename: S
authors.initials: S
authors.lastname: Gormley
authors.forename: C M
authors.initials: CM
authors.lastname: Kerskens
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D015283:Citalopram / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013113:Spin Labels
chemical_list: D018492:Dopamine Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013113:Spin Labels; D015283:Citalopram; D005277:Fenfluramine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010134:Fenclonine