Mechanisms mediating the ability of caffeine to influence MDMA ('Ecstasy')-induced hyperthermia in rats.
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.
Vanattou-Saïfoudine
N
N
Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
McNamara
R
R
Harkin
A
A
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
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