Dopamine D-1 Receptor-Mediated Intracellular Responses in the Hypothalamus after Co-Administration of Caffeine with MDMA

Markers of dopamine D1 receptor activation were determined to elucidate intracellular mechanisms associated with the combined effects of caffeine and 3,4 methylenedioxymethamphetamine (MDMA), reported previously to produce increased toxicity, when compared with either drug alone. Caffeine (10 mg/kg) and MDMA (15 mg/kg) were administered to male Sprague Dawley rats alone and in combination. One hour after drug administration, core body temperature and phosphorylation of the dopamine D1‐related intracellular markers, cAMP response element binding protein (CREB), the dopamine and c‐AMP‐regulated phosphoprotein of 32 kDa (DARPP‐32) and expression of the immediate early gene and cellular activation marker c‐fos were determined in the hypothalamus. Co‐administration of caffeine with MDMA increased core body temperature when compared with MDMA or caffeine treatment alone. Pre‐treatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg, i.p.), 30 min. prior to caffeine and MDMA administration, produced a hypothermic response to MDMA that was unaffected by caffeine. Co‐administration of caffeine with MDMA increased p‐CREB, p‐DARPP‐32 and c‐fos expression when compared with either treatment alone. Pre‐treatment with SCH‐23390 attenuated the changes in p‐CREB, p‐DARPP and c‐fos. The results show an enhanced intracellular response when caffeine is combined with MDMA but not with either agent alone suggestive of synergistic intracellular actions convergent on a dopamine D1 receptor signalling pathway. A dopamine‐related synergy associated with the combined administration of caffeine and MDMA may have important use and safety implications for recreational drug users.