Effect of adenosine receptors on 3, 4 methylene dioxy methamphetamine induced hyperthermic, neuroinflammatory and neurotoxic effects in mouse brain
Khairnar, Amit S. (2010) Effect of adenosine receptors on 3, 4 methylene dioxy methamphetamine induced hyperthermic, neuroinflammatory and neurotoxic effects in mouse brain. [Doctoral Thesis]
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Abstract
Previous studies of ours and other groups in mice have shown that 3, 4 Methylenedioxymethamphetamine (MDMA, ecstasy) produces neurotoxic damage to dopaminergic neurons and neuroinflammation and caffeine, an adenosine A1/A2A antagonist enhances glial activation induced by MDMA, suggesting potential facilitation of neurodegenerative processes. In the present study we want to investigate effect of caffeine on MDMA induced dopaminergic neurotoxicity in adult mice, whereas selective A1 ( DPCPX ) and A2A ( SCH58261 ) antagonist will be evaluated in adult mice only. C57BL/6J male mice were treated with MDMA (4x20 mg/kg, i.p.) at 2 h interval alone or in combination with caffeine (10 mg/kg, i.p.), SCH 58261( 0.5 mg/kg, i.p.), DPCPX (0.5 mg/kg, i.p.) or saline 30 mins before first and third administration of MDMA. Caffeine, SCH 58261, DPCPX was given for two more days after MDMA treatment. Mice were sacrificed 48 h after last administration of MDMA. Immunohistochemistry of tyrosine hydroxylase (TH), CD11b and glial fibrillary acidic protein (GFAP) were performed to detect dopaminergic neuronal damage, microglia and astroglia activation respectively in substantia nigra pars compacta (SNc) and striatum (CPu). Repeated administration of MDMA induced significant decrease (15%) in TH positive neurons in SNc as compare to vehicle. Association of caffeine, SCH 58261, DPCPX with MDMA did not further decrease TH positive neurons as compare to MDMA alone. MDMA induced significant increase in CD11b immunoreactivity in SNc and CPu and GFAP immunoreactivity in CPu as compare to vehicle in adult mice. Treatment with SCH 58261 significantly potentiated MDMA induced increase in CD11b immunoreactivity in both SNc and CPu, whereas SCH58261 did not alter MDMA induced GFAP immunoreactivity in CPu. In contrast, treatment with DPCPX significantly potentiated both MDMA induced increase in CD11b and GFAP immunoreactivity in CPu but not in SNc. Results suggest that association of MDMA plus caffeine could produce increase of MDMA toxicity and both A1 and A2A receptors are involved in the potentiation of MDMA-mediated neuroinflammatory but not neurodegenerative effects suggesting a role of adenosine in MDMA harmful effects
Furthermore to evaluate the influence of caffeine in MDMA-induced neurotoxicity, MDMA was acutely administered to mice, alone or in combination with caffeine. CD11b and GFAP immunoreactivity were evaluated as markers of microglia and astroglia activation in the substantia nigra pars-compacta (SNc) and striatum. MDMA was associated with significantly higher GFAP immunoreactivity in striatum and CD11b immunoreactivity in both areas. Caffeine potentiated the increase in CD11b and GFAP in the striatum but not in the SNc of MDMA-treated mice. The abuse of MDMA is a growing worldwide problem. The results of this study suggest that combination of MDMA plus caffeine by increasing glial activation might have harmful health consequences.
MDMA AND CAFFEINE: A LETHAL COMBINATION
K.M. O’Boyle, K. Murphy and J.J. Callanan1. UCD Schools of Biomolecular and Biomedical Sciences and 1Agriculture, Food Science and Veterinary Medicine, Conway Institute, University College Dublin, Belfield; Dublin 4, Ireland.
The ring-substituted amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a widely used drug of abuse that causes acute hyperlocomotion and hyperthermia and long-term serotonergic neurotoxicity (Green et al., 1995). The aim of the present study was to investigate whether MDMA-induced toxicity was altered by co-administration of caffeine, a CNS stimulant frequently contained in impure ecstasy tablets and also in caffeine-laced high energy drinks.
Male Wistar rats (250-350 g) received two i.p. injections at 60 min intervals: saline or 20 mg/kg caffeine i.p. followed by saline or 20 mg/kg MDMA. Rats were assessed for (i) acute hyperthermic effects of drug treatments using a Braun Thermoscan infrared aural thermometer with digital readout, (ii) changes in blood biochemistry using a wet chemistry analyser (Randox Daytona) and (iii) post-mortem for changes to vital organs.
All rats that were treated with 20 mg/kg MDMA (n=25) survived; however, 4/4 rats co-treated with 20 mg/kg caffeine and 20 mg/kg MDMA collapsed lost their righting reflex and died within 4 hr of administration of MDMA (p<0.0001; χ2 test). Thereafter, co-treated rats were euthansed 3 hr after administration of MDMA. MDMA increased rat aural temperature. The hyperthermic effect of MDMA was significantly enhanced by caffeine 1 hr after MDMA (Table 1). Administration of MDMA caused a significant increase in serum levels of urea and creatinine. These effects of MDMA were enhanced by co-administration of caffeine, which alone did not alter these parameters (Table 1). Both MDMA and caffeine increased serum potassium levels; however, serum levels of potassium in co-treated animals were similar to vehicle treated controls (Table 1).
Table 1. Effects of 20 mg/kg MDMA alone and in combination with 20 mg/kg caffeine
Saline/Saline 36.9 ± 0.5 7.7 ± 0.2 52.7 ± 4.9 8.3 ± 1.5
Caffeine/Saline 36.8 ±0.4 8.1 ± 0.6 67.5 ± 3.6
Saline/MDMA 37.3 ± 0.6 10.8 ± 2.6*** 98.1 ± 17.9*** 12.6 ± 1.8**
Caffeine/MDMA 39.2 ± 0.4$$$ 14.5 ± 0.8$$ 117.2 ± 3.8$
Temperature °C Urea mM Creatinine μM Potassium mM Temperature measurements were made 1 hr after the second injection. Data are means ± SEM, n= 3-8. **p<0.01, ***p<0.001 vs saline/saline, $p<0.05, $$p<0.01, $$$p<0.001 vs saline/MDMA, 1 way ANOVA followed by Bonferroni’s test
11.1 ± 1.2*
These data demonstrate that doses of caffeine and MDMA that individually are well tolerated by rats are lethal when administered together. The cause of death mediated by the drug combination remains to be established. However, the increased rate of rise of body temperature, as well as the changes to serum urea and creatinine levels that are indicative of acute renal damage, may be contributing factors.
In a recent study of the acute and chronic effects of MDMA, the possible interactions of caffeine and MDMA were examined. Caffeine exacerbated the acute hyperthermic response to MDMA and tended to increase the loss of serotonin (forebrain 5-HT or hydroxytryptamine) and 5-HIAA (5-hydroxyindoleacetic acid). Thus, caffeine may aggravate the hyperthermic and neurotoxic effects of MDMA, possibly through a mechanism involving dopamine release. It was also found that higher doses of caffeine (10 and 20 mg.kg-1 body mass) when co-administered with MDMA (20 mg.kg-1 body mass) had lethal effects in experimental animals.
These results suggest that caffeine enhances the effects of MDMA and could possibly exacerbate dehydration due to separate diuretic effects.
Read more:
http://www.drugs-forum.com/forum/showwiki.php?title=MDMA#ixzz1MIH4pXRi
The point is that its a terrible idea. I have witnessed this combo harm people time and time again. FYI neurotoxic effects are not noticeable until a certain threshold is crossed. For example it takes 80% of dopamine neurons to be lesioned before parkinsons manifests, but at say 50% dopaminergic signal loss there is still a large amount of damage going un-noticed until that red line is crossed.
Mixing any stimulant with MDMA is bad news. Mixing stims with MDA is even worse.....
I put this together VERY quick, but i can post more articles and anecdotes/ experiences if anyone wants to see or has doubts.
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