title: Continuous infusion of the α7 nicotinic acetylcholine receptor agonist EVP-6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study.
abstract: We investigated whether the effects of acutely administered EVP-6124, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay-dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.6 or 2 ng/ml, which were similar to the efficacious plasma concentrations after single-oral dosing. The 0.3 mg/kg acute dose enhanced memory at a total plasma concentration of ∼0.3 ng/ml at 1-4 h after dosing. Continuous treatment produced total plasma Css values of 0.48 and 1.93 ng/ml on day 6 and enhanced memory. At EVP-6124 plasma concentrations that optimally enhance memory in the object recognition task, tolerance did not develop after 6 days of continuous treatment.
authors: aFORUM Pharmaceuticals Inc., Watertown, Massachusetts, USA bSchool for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors: Nick P
authors: NP
authors: van Goethem
authors: Jos
authors: J
authors: Prickaerts
authors: Devin
authors: D
authors: Welty
authors: Dorothy G
authors: DG
authors: Flood
authors: Gerhard
authors: G
authors: Koenig
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004361:Drug Tolerance; D008297:Male; D023421:Models, Animal; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011812:Quinuclidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: C573817:7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor