title: Mechanisms mediating the ability of caffeine to influence MDMA ('Ecstasy')-induced hyperthermia in rats.
abstract: OBJECTIVE
  Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction.
  
  
  METHODS
  Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration.
  
  
  RESULTS
  Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia.
  
  
  CONCLUSIONS
  A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.
authors.affiliation: Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Vanattou-Saïfoudine
authors.forename: R
authors.initials: R
authors.lastname: McNamara
authors.forename: A
authors.initials: A
authors.lastname: Harkin
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D018759:Adrenergic Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D002110:Caffeine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology; D018490:Serotonin Agents / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D015259:Dopamine Agents; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D018490:Serotonin Agents; D012701:Serotonin; D002110:Caffeine; D018817:N-Methyl-3,4-methylenedioxyamphetamine