title: Extended-access methamphetamine self-administration elicits neuroinflammatory response along with blood-brain barrier breakdown.
abstract: Methamphetamine (METH) is a highly addictive psychostimulant drug that can lead to neurological and psychiatric abnormalities. Several studies have explored the central impact of METH use, but the mechanism(s) underlying blood-brain barrier (BBB) dysfunction and associated neuroinflammatory processes after chronic METH consumption are still unclear. Important findings in the field are mainly based on in vitro approaches and animal studies using an acute METH paradigm, and not much is known about the neurovascular alterations under a chronic drug use. Thus, the present study aimed to fill this crucial gap by exploring the effect of METH-self administration on BBB function and neuroinflammatory responses. Herein, we observed an increase of BBB permeability characterized by Evans blue and albumin extravasation in the rat hippocampus and striatum triggered by extended-access METH self-administration followed by forced abstinence. Also, there was a clear structural alteration of blood vessels showed by the down-regulation of collagen IV staining, which is an important protein of the endothelial basement membrane, together with a decrease of intercellular junction protein levels, namely claudin-5, occludin and vascular endothelial-cadherin. Additionally, we observed an up-regulation of vascular cell and intercellular adhesion molecule, concomitant with the presence of T cell antigen CD4 and tissue macrophage marker CD169 in the brain parenchyma. Rats trained to self-administer METH also presented a neuroinflammatory profile characterized by microglial activation, astrogliosis and increased pro-inflammatory mediators, namely tumor necrosis factor-alpha, interleukine-1 beta, and matrix metalloproteinase-9. Overall, our data provide new insights into METH abuse consequences, with a special focus on neurovascular dysfunction and neuroinflammatory response, which may help to find novel approaches to prevent or diminish brain dysfunction triggered by this overwhelming illicit drug.
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal. Electronic address: jgoncalves@fmed.uc.pt.
authors.forename: Joana
authors.initials: J
authors.lastname: Gonçalves
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Leitão
authors.affiliation: Department of Psychobiology, School of Psychology, UNED, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Higuera-Matas
authors.affiliation: Department of Psychobiology, School of Psychology, UNED, Madrid, Spain.
authors.forename: María Amparo
authors.initials: MA
authors.lastname: Assis
authors.affiliation: Department of Psychobiology, School of Psychology, UNED, Madrid, Spain.
authors.forename: Santiago M
authors.initials: SM
authors.lastname: Coria
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fontes-Ribeiro
authors.affiliation: Department of Psychobiology, School of Psychology, UNED, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ambrosio
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D062507:Claudin-5 / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D062793:Occludin / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration
chemical_list: D000697:Central Nervous System Stimulants; D062507:Claudin-5; D062793:Occludin; D008694:Methamphetamine
keywords: Astrocytes; Blood-brain barrier; Matrix metalloproteinase; Methamphetamine; Microglial cells