title: Carrier-mediated transport of the quaternary ammonium neuronal nicotinic receptor antagonist n,n'-dodecylbispicolinium dibromide at the blood-brain barrier.
abstract: The quaternary ammonium compound N,N'-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [(3)H]dopamine release and decreases nicotine self-administration, suggesting that this polar, charged molecule penetrates the blood-brain barrier (BBB). This report focuses on 1) BBB penetration of bPiDDB; 2) the mechanism of permeation; and 3) comparison of bPiDDB to the cations choline and N-octylnicotinium iodide (NONI), both of which are polar, charged molecules that undergo facilitated BBB transport. The BBB permeation of [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB was evaluated using in situ rat brain perfusion methods. Cerebrovascular permeability surface-area product (PS) values for [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB were comparable (1.33 +/- 0.1, 1.64 +/- 0.15, and 1.3 +/- 0.3 ml/s/g, respectively). To ascertain whether penetration was saturable, unlabeled substrate was added to the perfusion fluid. Unlabeled choline (500 microM) reduced the PS of [(3)H]choline to 0.15 +/- 0.06 microl/s/g (p < 0.01). Likewise, unlabeled bPiDDB (500 microM) reduced the PS of [(14)C]bPiDDB to 0.046 +/- 0.005 microl/s/g (p < 0.01), whereas unlabeled NONI reduced the PS for [(3)H]NONI by approximately 50% to 0.73 +/- 0.31 microl/s/g. The PS of [(14)C]bPiDDB was reduced (p < 0.05) in the presence of 500 microM choline, indicating that the BBB choline transporter may be responsible for the transport of bPiDDB into brain. Saturable kinetic parameters for [(14)C]bPiDDB were similar to those for [(3)H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for approximately 90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 S. Coulter Dr., Amarillo, TX 79106-1712, USA. paul.lockman@ttuhsc.edu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Manda
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.forename: Fancy
authors.initials: F
authors.lastname: Thomas
authors.forename: Zaineb Fadhel
authors.initials: ZF
authors.lastname: Albayati
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: David D
authors.initials: DD
authors.lastname: Allen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000378:metabolism*; D010847:Picolines / Q000378:metabolism*; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: C513964:N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide; D009419:Nerve Tissue Proteins; D018733:Nicotinic Antagonists; D010847:Picolines; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D011978:Receptors, Nicotinic; C075746:Slc6a8 protein, rat; D002794:Choline