Document Detail

Coexistence of passive and proton antiporter-mediated processes in nicotine transport at the mouse blood-brain barrier.
MedLine Citation:
PMID:  23212563     Owner:  NLM     Status:  MEDLINE    
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 [(3)H]-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.
Salvatore Cisternino; Hélène Chapy; Pascal André; Maria Smirnova; Marcel Debray; Jean-Michel Scherrmann
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Publication Detail:
Type:  Journal Article     Date:  2012-12-05
Journal Detail:
Title:  The AAPS journal     Volume:  15     ISSN:  1550-7416     ISO Abbreviation:  AAPS J     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-05     Completed Date:  2013-10-22     Revised Date:  2013-12-10    
Medline Journal Info:
Nlm Unique ID:  101223209     Medline TA:  AAPS J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  299-307     Citation Subset:  IM    
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MeSH Terms
ATP-Binding Cassette Transporters / deficiency,  drug effects,  genetics,  metabolism*
Antiporters / drug effects,  metabolism*
Binding, Competitive
Biological Transport
Blood-Brain Barrier / drug effects,  metabolism*
Diphenhydramine / metabolism
Hydrogen-Ion Concentration
Mice, Knockout
Models, Biological
Nicotine / metabolism*
Nonlinear Dynamics
Organic Cation Transport Proteins / deficiency,  drug effects,  genetics,  metabolism*
Tramadol / metabolism
Reg. No./Substance:
0/Antiporters; 0/Organic Cation Transport Proteins; 39J1LGJ30J/Tramadol; 54-11-5/Nicotine; 8GTS82S83M/Diphenhydramine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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