Influence of caffeine on 3,4‐methylenedioxymethamphetamine‐induced dopaminergic neuron degeneration and neuroinflammation is age‐dependent

Frau, Lucia; Costa, Giulia; Porceddu, Pier Francesca; Khairnar, Amit; Castelli, Paola; Ennas, Maria Grazia; Madeddu, Claudio; Wardas, Jadwiga; Morelli, Micaela

doi:10.1111/jnc.13377

Cited by 30 publications

(28 citation statements)

References 82 publications

(201 reference statements)

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“…In contrast, chronic low doses of caffeine exerted anti-inflammatory effects and prevented MDMA-induced neuroinflammatory reaction (Ruiz-Medina et al 2013 ). Study of Frau et al ( 2016 ) showed that caffeine potentiated MDMA-induced DA neuron degeneration and neuroinflammation in adolescent mice. Vanattou-Saïfoudine et al ( 2012 ) proposed that caffeine exacerbated adverse reactions induced by various psychostimulants, such as hyperthermia, tachycardia, and increased mortality as the result of increased DA release.…”

Section: Discussionmentioning

confidence: 99%

“…Our earlier results indicated that exacerbation of MDMA effect on DA and 5-HT release by caffeine in mice was mediated via adenosine A1 and A2A receptors (Górska and Gołembiowska 2015 ). The results of Khairnar et al ( 2010 ) and Frau et al ( 2016 ) demonstrated that neuroinflammatory response induced by MDMA in adult C57BL/6J mice and mice treated in adolescence with MDMA was potentiated by caffeine. The abovementioned data suggest that caffeine increases MDMA-related neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

et al. 2017

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MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. MDMA is often ingested with caffeine. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. To find out whether caffeine aggravates MDMA neurotoxicity, the content of DA and 5-HT, density of brain DAT and SERT, and oxidative damage of nuclear DNA were determined. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DNA damage was assayed with the alkaline comet assay. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open-field (OF) test and novel object recognition (NOR) test. Caffeine potentiated MDMA-induced DA release while inhibiting 5-HT release in the mouse striatum. Caffeine also exacerbated the oxidative damage of nuclear DNA induced by MDMA but diminished DAT decrease in the striatum and worsened a decrease in SERT density produced by MDMA in the frontal cortex. Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine. The exploration of novel object in the NOR test was diminished by MDMA and caffeine. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

et al. 2017

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“…The density of immunoreacted fibers was determined quantitatively using the ImageJ program (U.S. National Institutes of Health, USA). No significant differences in the density of immunoreacted fibers were seen between the three sections, thus values from different levels were averaged (Frau et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age

Costa

Pinna

Porceddu

et al. 2018

Front. Aging Neurosci.

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We have recently shown that male Rhes knockout (KO) mice develop a mild form of spontaneous Parkinson’s disease (PD)-like phenotype, characterized by motor impairment and a decrease in nigrostriatal dopamine (DA) neurons. Experimental evidence has implicated neuroinflammation in PD progression, and the presence of activated glial cells has been correlated with DA neuron degeneration. Despite this, several factors, such as gender, have been found to affect DAergic neuron degeneration and influence neuroinflammation, explaining the differences between men and women in the etiology of PD. On these basis, we studied age and gender differences in DA neuron degeneration and gliosis in the nigrostriatal system of adult (3-month-old) and middle aged (12-month-old) male and female Rhes wild-type (WT) and KO mice. Through immunohistochemistry, tyrosine hydroxylase (TH), microglial (complement type 3 receptor [CD11b]) and astroglial (glial fibrillary acid protein [GFAP]) increase, were evaluated. Adult male Rhes KO mice showed a decrease in TH and an increase in CD11b, both in the caudate putamen (CPu) and substantia nigra pars compacta (SNc), and an increase in GFAP in the CPu. In contrast, adult female Rhes KO mice showed only a decrease in TH in the SNc, whereas no modifications to the levels of GFAP and CD11b were observed in the CPu or SNc. Middle aged male Rhes KO mice showed a decrease in TH in the CPu and SNc, and an increase in GFAP and CD11b in the SNc. Middle aged female Rhes KO mice showed a decrease in TH in the CPu and SNc and an increase in CD11b only in the CPu, but no modifications to GFAP levels. The more marked DA neuron degeneration and neuroinflammation in male compared with female Rhes KO mice, while confirming the role of Rhes as an important protein for DA neuron survival, gives support to Rhes KO mice as a valuable preclinical model for studying the vulnerability factors of DA neuron degeneration as in PD.

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“…However, no reports are available showing cocaine treatment increasing reactive astrogliosis in the dorsal striatum. Moreover, other conditions where other psychostimulants were co-administered with caffeine reported that caffeine can potentiate astrogliosis in different SNC areas (Khairnar et al 2010; Frau et al 2015). We have found increased GFAP-positive astrocytes in the dorsal striatum after chronic psychostimulant treatment and after 7 days of withdrawal.…”

Section: Resultsmentioning

confidence: 97%

“…Even if many studies are not available reporting cocaine effects on astrocyte reactivity, GFAP has been previously demonstrated to be responsive to cocaine administration (Freeman et al 2010; Blanco-Calvo et al 2014). In addition, it was previously shown that caffeine enhanced astroglia and microglia reactivity induced by MDMA in the mouse striatum (Khairnar et al 2010) and that caffeine can potentiate MDMA-induced neurotoxicity (Frau et al 2015). Moreover, caffeine potentiated the neurotoxic effects of methamphetamine (Sinchai et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Combined Effects of Simultaneous Exposure to Caffeine and Cocaine in the Mouse Striatum

et al. 2016

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Caffeine is the world’s most popular psychoactive drug and is also an active adulterant found in many drugs of abuse, including seized cocaine samples. Despite several studies which examine the effects of caffeine or cocaine administered as single agents, little data are available for these agents when given in combination. The purpose of the present study was to determine if combined intake of both psychostimulants can lead to maladaptive changes in striatal function. Mice were injected with a binge regimen (intermittent treatment for 13 days) of caffeine (3 × 5 mg/kg), cocaine (3 × 10 mg/kg), or combined administration. We found that chronic caffeine potentiated locomotion induced by cocaine and that both caffeine-treated groups showed sensitization. Striatal tissue was obtained 24 h and 7 days after last injection (withdrawal) for immunohistochemistry and mRNA expression. Our results show that combined intake of both psychostimulants can increase GFAP immunoreactivity in the striatum at both times post treatment. Gene expression analysis, targeted at dopamine, adenosine, and glutamate receptor subunit genes, revealed significant transcript down-regulation in the dorsal striatum of AMPA, NMDA, D1 and D2 receptor subunit mRNA expression in the group that received combined treatment, but not after individual administration. At withdrawal, we found increased D1 receptor mRNA expression along with increased A1, AMPA, NMDA, and metabotropic subunit expression. A2A mRNA showed decreased expression after both times in all experimental groups. Our study provides evidence that there are striatal alterations mediated by combined caffeine and cocaine administration, and highlights negative outcomes of chronic intake of both psychostimulants.

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Influence of caffeine on 3,4‐methylenedioxymethamphetamine‐induced dopaminergic neuron degeneration and neuroinflammation is age‐dependent

Cited by 30 publications

References 82 publications

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age

Combined Effects of Simultaneous Exposure to Caffeine and Cocaine in the Mouse Striatum

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