The AAPS Journal

, Volume 15, Issue 2, pp 299–307 | Cite as

Coexistence of Passive and Proton Antiporter-Mediated Processes in Nicotine Transport at the Mouse Blood–Brain Barrier

  • Salvatore CisterninoEmail author
  • Hélène Chapy
  • Pascal André
  • Maria Smirnova
  • Marcel Debray
  • Jean-Michel Scherrmann
Research Article


Nicotine, the main tobacco alkaloid leading to smoking dependence, rapidly crosses the blood–brain barrier (BBB) to become concentrated in the brain. Recently, it has been shown that nicotine interacts with some organic cation transporters (OCT), but their influence at the BBB has not yet been assessed in vivo. In this study, we characterized the transport of nicotine at the mouse luminal BBB by in situ brain perfusion. Its influx was saturable and followed the Michaelis–Menten kinetics (K m = 2.60 mM, V max = 37.60 nmol/s/g at pH 7.40). At its usual micromolar concentrations in the plasma, most (79%) of the net transport of nicotine at the BBB was carrier-mediated, while passive diffusion accounted for 21%. Studies on knockout mice showed that the OCT Oct1–3, P-gp, and Bcrp did not alter [3H]-nicotine transport at the BBB. Neither did inhibiting the transporters Mate1, Octn, or Pmat. The in vivo manipulation of intracellular and/or extracellular pH, the chemical inhibition profile, and the trans-stimulation experiments demonstrated that the nicotine transporter at the BBB shared the properties of the clonidine/proton antiporter. The molecular features of this proton-coupled antiporter have not yet been identified, but it also transports diphenhydramine and tramadol and helps nicotine cross the BBB at a faster rate and to a greater extent. The pharmacological inhibition of this nicotine/proton antiporter could represent a new strategy to reduce nicotine uptake by the brain and thus help curb addiction to smoking.


blood–brain barrier nicotine organic cation proton antiporter transporter 



We thank Dr. Alfred H. Schinkel for supplying the knockout mice, GSK for generously supplying GF120918, and Novartis for generously supplying PSC833. We thank Dr. S. Rasika for editing the English text.

Conflict of Interest

No conflict of interest.


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Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Salvatore Cisternino
    • 1
    • 2
    Email author
  • Hélène Chapy
    • 1
  • Pascal André
    • 1
    • 2
  • Maria Smirnova
    • 1
  • Marcel Debray
    • 1
  • Jean-Michel Scherrmann
    • 1
    • 2
  1. 1.INSERM U705, CNRS UMR 8206, Pharmacocinétique, Faculté de Pharmacie, Sorbonne Paris Cité, Université Paris DiderotUniversité Paris DescartesParisFrance
  2. 2.Assistance publique des hôpitaux de Paris, AP-HPParisFrance

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