Studies on the mechanisms underlying amiloride enhancement of 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats.
Beatriz Goñi-allo, Elena Puerta, Isabel Hervias, Richard Di Palma, Maria Ramos, Berta Lasheras, Norberto Aguirre
European Journal of Pharmacology May 21, 2007 DOI: 10.1016/j.ejphar.2007.01.049 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Amiloride MDMA dimethylamiloride fluoxetine flunarizine diltiazem |
| Dose | 2.5 mg/kg amiloride every 2 h x 3 i.p.; 5 mg/kg MDMA every 2 h x 3 i.p.; 10 mg/kg fluoxetine i.p. |
| Topics | MDMA Serotonin |
| Citations | 13 |
| Key findings | Amiloride exacerbates MDMA-induced serotonin loss in rats primarily by enhancing MDMA-induced hyperthermia, and this effect is mediated by blockade of Na(+)/H(+) exchange. |
Abstract
Amiloride and several of its congeners known to block the Na(+)/Ca(2+) and/or Na(+)/H(+) antiporters potentiate methamphetamine-induced neurotoxicity without altering methamphetamine-induced hyperthermia. We now examine whether amiloride also exacerbates 3,4-methylenedioxymethamphetamine (MDMA)-induced long-term serotonin (5-HT) loss in rats. Amiloride (2.5 mg/kg, every 2 h x 3, i.p.) given at ambient temperature 30 min before MDMA (5 mg/kg, every 2 h x 3, i.p.), markedly exacerbated long-term 5-HT loss. However, in contrast to methamphetamine, amiloride also potentiated MDMA-induced hyperthermia. Fluoxetine (10 mg/kg i.p.) completely protected against 5-HT depletion caused by the MDMA/amiloride combination without significantly altering the hyperthermic response. By contrast, the calcium channel antagonists flunarizine or diltiazem did not afford any protection. Findings with MDMA and amiloride were extended to the highly selective Na(+)/H(+) exchange inhibitor dimethylamiloride, suggesting that the potentiating effects of amiloride are probably mediated by the blockade of Na(+)/H(+) exchange. When the MDMA/amiloride combination was administered at 15 degrees C hyperthermia did not develop and brain 5-HT concentrations remained unchanged 7 days later. Intrastriatal perfusion of MDMA (100 microM for 8 h) in combination with systemic amiloride caused a small depletion of striatal 5-HT content in animals made hyperthermic but not in the striatum of normothermic rats. These data suggest that enhancement of MDMA-induced 5-HT loss caused by amiloride or dimethylamiloride depends on their ability to enhance MDMA-induced hyperthermia. We hypothesise that blockade of Na(+)/H(+) exchange could synergize with hyperthermia to render 5-HT terminals more vulnerable to the toxic effects of MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain Journal of Neuroscience Research September 21, 2011
- Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation Pharmaceuticals July 5, 2011
- Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat. Journal of Neurochemistry February 2009
- On the Mechanisms Underlying 3,4-Methylenedioxymethamphetamine Toxicity: The Dilemma of the Chicken and the Egg Neuropsychobiology 2009
Cites 25
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- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Journal of Neuroscience June 15, 1999
and 20 more in the library