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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† and Norberto Aguirre*,‡
*Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain
†Group of Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha Regional Centre for Biomedical Research, Albacete, Spain
‡Division of Neuroscience, CIMA, School of Medicine, University of Navarra, Pamplona, Spain
Address correspondence and reprint requests to Norberto Aguirre, Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, Pamplona 31008, Spain. E-mail: [email protected]
Copyright Journal compilation © 2009 International Society for Neurochemistry
KEYWORDS
3,4-methylenedioxymethamphetamine • 5-hydroxytryptamine • mitochondrial ATP-sensitive K+ channels • phosphodiesterase 5 inhibitor • protein kinase G • sildenafil • vardenafil
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 × 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.
Elena Puerta*, Isabel Hervias*, Beatriz Goñi-Allo*, Berta Lasheras*, Joaquin Jordan† and Norberto Aguirre*,‡
*Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain
†Group of Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha Regional Centre for Biomedical Research, Albacete, Spain
‡Division of Neuroscience, CIMA, School of Medicine, University of Navarra, Pamplona, Spain
Address correspondence and reprint requests to Norberto Aguirre, Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, Pamplona 31008, Spain. E-mail: [email protected]
Copyright Journal compilation © 2009 International Society for Neurochemistry
KEYWORDS
3,4-methylenedioxymethamphetamine • 5-hydroxytryptamine • mitochondrial ATP-sensitive K+ channels • phosphodiesterase 5 inhibitor • protein kinase G • sildenafil • vardenafil
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 × 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.
