title: Dopamine D1 receptor-mediated intracellular responses in the hypothalamus after co-administration of caffeine with MDMA.
abstract: Markers of dopamine D(1)  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 D(1) -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 D(1)  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 D(1)  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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Vanattou-Saïfoudine
authors.forename: Brendan
authors.initials: B
authors.lastname: Behan
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D002110:Caffeine; D018817:N-Methyl-3,4-methylenedioxyamphetamine