title: Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Puerta
authors.forename: Isabel
authors.initials: I
authors.lastname: Hervias
authors.forename: Beatriz
authors.initials: B
authors.lastname: Goñi-Allo
authors.forename: Berta
authors.initials: B
authors.lastname: Lasheras
authors.forename: Joaquin
authors.initials: J
authors.lastname: Jordan
authors.forename: Norberto
authors.initials: N
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006213:Hallucinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D054086:KATP Channels / Q000187:drug effects; D008297:Male; D008845:Microinjections; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000172:deficiency*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D006213:Hallucinogens; D007093:Imidazoles; D054086:KATP Channels; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D050486:Serotonin Plasma Membrane Transport Proteins; D013450:Sulfones; D014227:Triazines; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D018817:N-Methyl-3,4-methylenedioxyamphetamine