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‐HT 2 receptor agonist DOI (2 mg·kg −1 ) but not following either agents alone. Pretreatment with the dopamine D 1 receptor antagonist Schering (SCH) 23390 (1 mg·kg −1 ), the 5‐HT 2 receptor antagonist ketanserin (5 mg·kg −1 ) or α 1 ‐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 A 1/2 receptor antagonist 9‐chloro‐2‐(2‐furanyl)‐[1,2,4]triazolo[1,5‐C]quinazolin‐5‐amine 15943 (10 mg·kg −1 ) or the A 2A receptor antagonist SCH 58261 (2 mg·kg −1 ) but not the A 1 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 A 2A receptor antagonism and PDE inhibition can account for the exacerbation of MDMA‐induced hyperthermia by caffeine.