Mechanisms mediating the ability of caffeine to influence MDMA (‘Ecstasy’)‐induced hyperthermia in rats

Background and purpose:  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. Experimental approach:  Adult male Sprague-Dawley rats were treated with caffeine (10 mg·kg−1; i.p.) and MDMA (15 mg·kg−1; i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration. Key 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·kg−1) was combined with the 5-HT releaser d-fenfluramine (5 mg·kg−1) or the non-selective dopamine receptor agonist apomorphine (1 mg·kg−1) was combined with the 5-HT2 receptor agonist DOI (2 mg·kg−1) but not following either agents alone. Pretreatment with the dopamine D1 receptor antagonist Schering (SCH) 23390 (1 mg·kg−1), the 5-HT2 receptor antagonist ketanserin (5 mg·kg−1) or α1-adreno- receptor antagonist prazosin (0.2 mg·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·kg−1) and the adenosine A1/2 receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg·kg−1) or the A2A receptor antagonist SCH 58261 (2 mg·kg−1) but not the A1 receptor antagonist DPCPX (10 mg·kg−1) exacerbated MDMA-induced hyperthermia. Conclusions and implications:  A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A2A receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.