title: Carrier-mediated cocaine transport at the blood-brain barrier as a putative mechanism in addiction liability.
abstract: BACKGROUND
  The rate of entry of cocaine into the brain is a critical factor that influences neuronal plasticity and the development of cocaine addiction. Until now, passive diffusion has been considered the unique mechanism known by which cocaine crosses the blood-brain barrier.
  
  
  METHODS
  We reassessed mechanisms of transport of cocaine at the blood-brain barrier using a human cerebral capillary endothelial cell line (hCMEC/D3) and in situ mouse carotid perfusion.
  
  
  RESULTS
  Both in vivo and in vitro cocaine transport studies demonstrated the coexistence of a carrier-mediated process with passive diffusion. At pharmacological exposure level, passive diffusion of cocaine accounted for only 22.5% of the total cocaine influx in mice and 5.9% in hCMEC/D3 cells, whereas the carrier-mediated influx rate was 3.4 times greater than its passive diffusion rate in vivo. The functional identification of this carrier-mediated transport demonstrated the involvement of a proton antiporter that shared the properties of the previously characterized clonidine and nicotine transporter. The functionnal characterization suggests that the solute carrier (SLC) transporters Oct (Slc22a1-3), Mate (Slc47a1) and Octn (Slc22a4-5) are not involved in the cocaine transport in vivo and in vitro. Diphenhydramine, heroin, tramadol, cocaethylene, and norcocaine all strongly inhibited cocaine transport, unlike benzoylecgonine. Trans-stimulation studies indicated that diphenhydramine, nicotine, 3,4-methylenedioxyamphetamine (ecstasy) and the cathinone compound 3,4-methylenedioxypyrovalerone (MDPV) were also substrates of the cocaine transporter.
  
  
  CONCLUSIONS
  Cocaine transport at the BBB involves a proton-antiporter flux that is quantitatively much more important than its passive diffusion. The molecular identification and characterization of this transporter will provide new tools to understand its role in addictive mechanisms.
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Hélène
authors.initials: H
authors.lastname: Chapy
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Maria
authors.initials: M
authors.lastname: Smirnova
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Pascal
authors.initials: P
authors.lastname: André
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Joël
authors.initials: J
authors.lastname: Schlatter
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Fouad
authors.initials: F
authors.lastname: Chiadmi
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud).
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM, U1144, 75006 Paris, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Descartes, UMR-S 1144, Paris, F-75006, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Université Paris Diderot, UMR-S 1144, Paris, F-75013, France (Drs. Chapy, Smirnova, André, Scherrmann, Declèves, Cisternino); Assistance publique hôpitaux de Paris, AP-HP, Jean Verdier, Bondy, F-93140, France (Drs. Schlatter, Chiadmi, Cisternino); INSERM, U1016, Institut Cochin, 75014, Paris, France (Dr. Couraud); CNRS, UMR8104, Paris, France (Dr. Couraud); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (Dr. Couraud). salvatore.cisternino@jvr.aphp.fr.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003042:Cocaine / Q000493:pharmacokinetics*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D004058:Diffusion; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2
chemical_list: D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse; D003042:Cocaine
keywords: biological transport; blood-brain barrier; cocaine; drug of abuse; pharmacokinetics.