title: Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent.
abstract: Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL-1β, and TNF-α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-α levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Frau
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Pier Francesca
authors.initials: PF
authors.lastname: Porceddu
authors.affiliation: Applied Neuroscience Research Group, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Amit
authors.initials: A
authors.lastname: Khairnar
authors.affiliation: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Castelli
authors.affiliation: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ennas
authors.affiliation: Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Madeddu
authors.affiliation: Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Wardas
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.|CNR, Institute of Neuroscience, Cagliari, Italy.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morelli
mesh_terms: D000367:Age Factors; D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004357:Drug Synergism; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology
chemical_list: D002110:Caffeine; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: adolescence; caudate-putamen; cytokines; nitric oxide; substantia nigra; tyrosine hydroxylase