title: Chronic nicotine exposure alters blood-brain barrier permeability and diminishes brain uptake of methyllycaconitine.
abstract: Methyllycaconitine (MLA) is reported to be a selective antagonist for the nicotinic acetylcholine receptor alpha7 subtype and has been found in animal behavioral studies to reduce nicotine self-administration and attenuate nicotine withdrawal symptoms. While MLA crosses the blood-brain barrier (BBB), no studies have assessed brain uptake in animals subjected to chronic nicotine exposure. Given that chronic nicotine administration has been reported to alter BBB parameters that may affect the kinetic BBB passage of MLA, we evaluated MLA brain uptake in naive and S-(-)nicotine-exposed rats (4.5 mg/kg/day for 28 days; osmotic minipumps) using in situ rat brain perfusions. Our results demonstrate that in situ(3)H-MLA brain uptake rates in naive animals approximate to intravenous kinetic data (K(in), 3.24 +/- 0.71 x 10(-4) mL/s/g). However, 28-day nicotine exposure diminished (3)H-MLA brain uptake by approximately 60% (K(in), 1.29 +/- 0.4 x 10(-4) mL/s/g). This reduction was not related to nicotine-induced (3)H-MLA brain efflux or BBB transport alterations. Similar experiments also demonstrated that the passive permeation of (14)C-thiourea was diminished approximately 24% after chronic nicotine exposure. Therefore, it appears that chronic nicotine exposure diminishes the blood-brain passive diffusion of compounds with very low extraction rates (i.e. permeability-limited compounds). These findings imply that the pharmacokinetics of neuropharmaceutical agents that are permeability limited may need to be re-evaluated in individuals exposed to nicotine.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, USA. paul.lockman@ttuhsc.edu
authors.forename: P R
authors.initials: PR
authors.lastname: Lockman
authors.forename: C J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: T J
authors.initials: TJ
authors.lastname: Abbruscato
authors.forename: D D
authors.initials: DD
authors.lastname: Allen
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D015918:Infusion Pumps, Implantable; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C054634:methyllycaconitine; D009538:Nicotine; D000157:Aconitine