PMID- 24626059 OWN - NLM STAT- MEDLINE DCOM- 20150414 LR - 20161020 IS - 1469-5111 (Electronic) IS - 1461-1457 (Linking) VI - 17 IP - 8 DP - 2014 Aug TI - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors. PG - 1243-55 LID - 10.1017/S1461145714000145 [doi] AB - The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1beta levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA-induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix. FAU - Rubio-Araiz, Ana AU - Rubio-Araiz A AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Perez-Hernandez, Mercedes AU - Perez-Hernandez M AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Urrutia, Andres AU - Urrutia A AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Porcu, Francesca AU - Porcu F AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Borcel, Erika AU - Borcel E AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Gutierrez-Lopez, Maria Dolores AU - Gutierrez-Lopez MD AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - O'Shea, Esther AU - O'Shea E AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. FAU - Colado, Maria Isabel AU - Colado MI AD - Departamento de Farmacologia, Facultad de Medicina,Universidad Complutense, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), Red de Trastornos Adictivos del Instituto de Salud Carlos III,Madrid,Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140314 PL - England TA - Int J Neuropsychopharmacol JT - The international journal of neuropsychopharmacology JID - 9815893 RN - 0 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine) RN - 0 (Collagen Type IV) RN - 0 (Immunoglobulin G) RN - 0 (Laminin) RN - 0 (Purinergic P2X Receptor Agonists) RN - 0 (Purinergic P2X Receptor Antagonists) RN - 0 (Pyridines) RN - 0 (Receptors, Purinergic P2X7) RN - 0 (Rosaniline Dyes) RN - 0 (Tetrazoles) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) RN - M1ZRX790SI (coomassie Brilliant Blue) SB - IM MH - Animals MH - Blood-Brain Barrier/*drug effects/*metabolism MH - Body Temperature/drug effects MH - Collagen Type IV/metabolism MH - Dentate Gyrus/drug effects/metabolism MH - Hippocampus/drug effects/metabolism MH - Immunoglobulin G/metabolism MH - Laminin/metabolism MH - Male MH - Matrix Metalloproteinase 3/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Microglia/metabolism MH - N-Methyl-3,4-methylenedioxyamphetamine/antagonists & inhibitors/*toxicity MH - Purinergic P2X Receptor Agonists/*toxicity MH - Purinergic P2X Receptor Antagonists/pharmacology MH - Pyridines/pharmacology MH - Rats MH - Receptors, Purinergic P2X7/*metabolism MH - Rosaniline Dyes/metabolism MH - Tetrazoles/pharmacology EDAT- 2014/03/15 06:00 MHDA- 2015/04/15 06:00 CRDT- 2014/03/15 06:00 PHST- 2014/03/15 06:00 [entrez] PHST- 2014/03/15 06:00 [pubmed] PHST- 2015/04/15 06:00 [medline] AID - S1461145714000145 [pii] AID - 10.1017/S1461145714000145 [doi] PST - ppublish SO - Int J Neuropsychopharmacol. 2014 Aug;17(8):1243-55. doi: 10.1017/S1461145714000145. Epub 2014 Mar 14.