PHYSIOPATHOLOGIE ET CIBLES THÉRAPEUTIQUES DE LA BARRIÈRE HÉMATO-ENCÉPHALIQUE

Leader

Research center

4 avenue de l'Observatoire
75006 Paris

Institution

Inserm
Université Paris Descartes
Université Paris Diderot
MTCI 563

Laboratory

Variabilité de réponses aux psychotropes
UMRS1144

Mots clefs

brain interfaces, psychotropic drugs, psychiatric disorders, transporters, biomarkers
Available to host a PhD student

publications

Jacob A, Hartz AM, Potin S, Coumoul X, Yousif S, Scherrmann JM, Bauer B, Declèves X. (2011) Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels. Fluids Barriers CNS. Aug 25;8:23.

Ball K, Bouzom F, Scherrmann JM, Walther B, Declèves X. (2012) Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone. J Pharm Sci. 101:4277-92

Yousif S, Chaves C, Potin S, Scherrmann JM, Declèves X. (2012) Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation. J Neurochem. 123:491-503

Mérian J, Boisgard R, Decleves X, Thezé B, Texier I, Tavitian B. Synthetic lipid nanoparticles targeting steroid organs. J Nucl Med. 2013 Nov;54(11):1996-2003.

Ball K, Bouzom F, Scherrmann JM, Walther B, Declèves X. A Physiologically Based Modeling Strategy during Preclinical CNS Drug Development. Mol Pharm. 2014 Jan 29.

Fields of research

Neuropharmacology / cell signaling

Research Theme

L’équipe développe une recherche fondamentale visant à étudier deux fonctions essentielles de la BHE : le maintien de l’homéostasie cérébrale vis-à-vis de composés endogènes et le contrôle de l’exposition cérébrale aux médicaments psychotropes.

Grâce à une approche expérimentale intégrée du gène à la fonction dans des modèles rongeursin vivo et in vitro (tissus isolés et modèles cellulaires humains), les mécanismes moléculaires régulant l’expression et l’activité des transporteurs et enzymes de la BHE ainsi que les conséquences fonctionnelles de ces modulations sont étudiés dans le cadre d’exposition à des drogues d’abus, de pathologies psychiatriques et/ou de leurs traitements en lien avec les deux orientations de recherche « addiction » et « maladie bipolaire » de l’Unité.

Membres de l'équipe

Fanchon BOURASSET
Stéphanie CHASSEIGNEAUX
Salvatore CISTERNINO
Benoit HOSTEN
Aude JACOB
Marie-Claude MENET
Nathalie RIZZO
Bruno SAUBAMEA
Jean-Michel SCHERRMANN

Lab rotation

Role of the brain neurovascular unit in Vulnerability to addiction to the psychostimulant drugs

Chercheur responsable: 

DECLEVES Xavier

Dates: 

4 April 2016 - 30 June 2016

Date limite de candidature: 

4 April 2016

Project:

Addiction to psychostimulant drugs is a complex disorder lacking of effective treatments. Due to the sustained increase in cocaine use and to the alarming spread on the drug market of new psychoactive substances including synthetic cathinones, identification of the mechanisms responsible for vulnerability to stimulant drug dependence is becoming mandatory to better understand the complex mechanisms underlying addiction to these drugs. Investigating vulnerability and dependence in a rat model of addiction to stimulant drugs will enable us to determine possible molecular targets to improve management of dependence to these drugs. Clinical and preclinical studies have demonstrated the critical role of the rate of the drug delivery to the brain in the resulting neuronal plasticity, reward effects and addiction liability [1,2]. Slowing the brain delivery rate of the drug of abuse is known as the “pharmacokinetic (PK) strategy” using drug-specific blood trapping (e.g. vaccine/immune strategy) or increasing its metabolism [3]. Recent studies of the team also illustrated the role of the blood-brain barrier (BBB) drug transporters and their critical rate-regulatory component in the brain uptake of psychoactive drugs [4,5].In this project we will study the role of the different endothelial and glial cells of the brain neurovascular unit and their plasticity with a multidisciplinary approach (behavior studies, pharmacokinetics, neurochemistry, and molecular biology).

[1] Samaha AN, Robinson TE. 2005 Why does the rapid delivery of drugs to the brain promote addiction?Trends Pharmacol Sci.[2] Volkow ND, Wang GJ, Fowler JS, Tomasi D, Baler R. 2012 Food and drug reward: overlapping circuits in human obesity and addiction. Curr Top Behav Neurosci.[3] Gorelick DA. 2012 Pharmacokinetic strategies for treatment of drug overdose and addiction. Future Med Chem.[4] Seleman M(1), Chapy H, Cisternino S, Courtin C, Smirnova M, Schlatter J, Chiadmi F, Scherrmann JM, Noble F, Marie-Claire C. 2014 Impact of P-glycoprotein at the blood-brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties.[5] Chapy H, Smirnova M, André P, Schlatter J, Chiadmi F, Couraud PO, Scherrmann JM, Declèves X, Cisternino S. 2014 Carrier-mediated cocaine transport at the blood-brain barrier as a putative mechanism in addiction liability. Int J Neuropsychopharmacol.




Address: Faculté de Pharmacie – 4 Av de l’Observatoire – 75006 Paris

Phone: (33) 1 53 73 99 91

Email: xavier.decleves@parisdescartes.fr

Website

 

 

 

Superviseur: 

Xavier DESCLEVES & Salvatore CISTERNINO