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.

Pharmacophore‐based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line

“…[ 3 H]‐clonidine (2.27 MBq·mmol −1 ), [ 3 H]‐naloxone (2.06 MBq·mmol −1 ) and [ 3 H]‐(−)cocaine (1.31 MBq·mmol −1 ) were purchased from Perkin Elmer (Courtaboeuf, France). Drugs were obtained as reported (Chapy et al , ). Compounds 1 to 10 were purchased from Specs (Delft, the Netherlands), and other chemicals were from Sigma (Saint Quentin‐Fallavier, France).…”

“…Brain microdialysis studies suggested that this DPH influx is present in rat, dog and non‐human primate BBB (Sadiq et al , ; Shaffer et al , ). In vitro studies of rodent and human immortalized brain endothelium and intestinal cell lines established the presence of a cationic drug/proton antiporter with unique properties that did not correspond to any known SLC transporters: OCT1‐3 (SLC22A1‐3), OCTN (SLC22A4‐5) and MATE1 (SLC47A1) (Fischer et al , ; Kuwayama et al , ; Okura et al , ; Chapy et al , ). In vivo/in situ studies definitively confirmed that a functional novel drug/proton antiporter, molecularly unknown, is physiologically active at the mouse BBB and blood–retina barrier (André et al , ; Chapy et al , ).…”

“…Clonidine has been characterized as a specific proton‐antiporter substrate at the mice BBB (André et al , ) and in various cell lines, including Caco‐2 cells (Fischer et al , ). This polyspecific transporter mediates the transport of at least nicotine and cocaine (André et al , ; Cisternino et al , ; Chapy et al , ), and ecstasy (MDMA) and heroin have also been suggested to be substrates (Chapy et al , , ).…”

“…The development of potent and selective inhibitors of the proton antiporter could reduce its transport activity and drop/lower the rate of substrates influx into the brain. Some CNS compounds, like imipramine, have been shown to be potent inhibitors of this transporter in vitro and/or in situ (Chapy et al , ). However, the high concentrations of these drugs needed to significantly inhibit this antiporter precludes any wanted or unwanted drug‐drug interactions induced by their systemic administration in vivo .…”

Neurotoxicology of Synthetic Cathinone Analogs

“…The rate at which drugs reach the brain parenchyma depends not only on their route of administration but also on their ability to cross the cerebral endothelium, also called the blood–brain barrier (BBB), which constitutes the main brain interface modulating the exchange of compounds between the brain and blood [50]. Alterations in BBB function are likely involved in drug abuse neurotoxicity [1, 86].…”