Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat.
Elena Puerta, Isabel Hervias, Beatriz Goñi-allo, Berta Lasheras, Joaquin Jordan, Norberto Aguirre
Journal of Neurochemistry February 2009 DOI: 10.1111/j.1471-4159.2008.05825.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in rats Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Sildenafil citrate MDMA KT5823 8-bromoguanosine cyclic 3' 5'-monophosphate 5-hydroxydecanoic acid wortmannin L-N5-(1-iminoethyl)-L-ornithine dihydrochloride vardenafil |
| Dose | sildenafil citrate 1.5 or 8 mg/kg; MDMA 3 x 5 mg/kg, i.p., every 2 h |
| Topics | MDMA Serotonin |
| Key findings | Sildenafil dose-dependently protected against MDMA-induced long-term depletion of indoles (serotonin) in rat striatum, frontal cortex, and hippocampus without altering MDMA-induced acute hyperthermia. The protection appears to require cGMP, PKG activation, and mitochondrial ATP-sensitive K+ channel opening, but not the Akt/eNOS/sGC pathway; vardenafil showed similar protection. |
Abstract
Phosphodiesterase 5 (PDE5) inhibitors are often used in combination with club drugs such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). We investigated the consequences of such combination in the serotonergic system of the rat. Oral administration of sildenafil citrate (1.5 or 8 mg/kg) increased brain cGMP levels and protected in a dose-dependent manner against 5-hydroxytryptamine depletions caused by MDMA (3 x 5 mg/kg, i.p., every 2 h) in the striatum, frontal cortex and hippocampus without altering the acute hyperthermic response to MDMA. Intrastriatal administration of the protein kinase G (PKG) inhibitor, KT5823 [(9S, 10R, 12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester)], suppressed sildenafil-mediated protection. By contrast, the cell permeable cGMP analogue, 8-bromoguanosine cyclic 3',5'-monophosphate, mimicked sildenafil effects further suggesting the involvement of the PKG pathway in mediating sildenafil protection. Because mitochondrial ATP-sensitive K(+) channels are a target for PKG, we next administered the specific mitochondrial ATP-sensitive K(+) channel blocker, 5-hydroxydecanoic acid, 30 min before sildenafil. 5-hydroxydecanoic acid completely reversed the protection afforded by sildenafil, thereby implicating the involvement of mitochondrial ATP-sensitive K(+) channels. Sildenafil also increased Akt phosphorylation, and so the possible involvement of the Akt/endothelial nitric oxide synthase (eNOS)/sGC signalling pathway was analysed. Neither the phosphatidylinositol 3-kinase inhibitor, wortmannin, nor the selective eNOS inhibitor, L-N5-(1-iminoethyl)-L-ornithine dihydrochloride, reversed the protection afforded by sildenafil, suggesting that Akt/eNOS/sGC cascade does not participate in the protective mechanisms. Our data also show that the protective effect of sildenafil can be extended to vardenafil, another PDE5 inhibitor. In conclusion, sildenafil protects against MDMA-induced long-term reduction of indoles by a mechanism involving increased production of cGMP and subsequent activation of PKG and mitochondrial ATP-sensitive K(+) channel opening.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- A review on the mitochondrial toxicity of “ecstasy” (3,4-methylenedioxymethamphetamine, MDMA) Current Research in Toxicology May 27, 2022
- 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
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and 7 more in the library