title: An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine.
abstract: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model.
  
  
  
  In this double-blind, placebo-controlled, four-way cross-over trial, 12 healthy male subjects received oral mecamylamine 10 and 20 mg, intravenous scopolamine 0.5 mg and placebo. Pharmacokinetics were analysed using non-compartmental analysis. Pharmacodynamic effects were measured with a multidimensional test battery that includes neurophysiological, subjective, (visuo)motor and cognitive measurements.
  
  
  
  All treatments were safe and well tolerated. Mecamylamine had a tmaxof 2.5 h and a Cmaxof 64.5 ng ml-1for the 20 mg dose. Mecamylamine had a dose-dependent effect decreasing the adaptive tracking performance and VAS alertness, and increasing the finger tapping and visual verbal learning task performance time and errors. Scopolamine significantly affected almost all pharmacodynamic tests.
  
  
  
  This study demonstrated that mecamylamine causes nicotinic receptor specific temporary decline in cognitive functioning. Compared with the scopolamine model, pharmacodynamic effects were less pronounced at the dose levels tested; however, mecamylamine caused less sedation. The cognitive effects of scopolamine might at least partly be caused by sedation. Whether the mecamylamine model can be used for proof-of-pharmacology of nicotinic acetylcholine receptor agonists remains to be established.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Anne Catrien
authors.initials: AC
authors.lastname: Baakman
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Ricardo
authors.identifier: 0000-0001-7581-7566
authors.initials: R
authors.lastname: Alvarez-Jimenez
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Rissmann
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Klaassen
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Sebastiaan C
authors.identifier: 0000-0003-3369-6107
authors.initials: SC
authors.lastname: Goulooze
authors.affiliation: Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jeroen C G
authors.initials: JCG
authors.lastname: den Burger
authors.affiliation: Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Eleonora L
authors.initials: EL
authors.lastname: Swart
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Joop M A
authors.initials: JMA
authors.lastname: van Gerven
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects*; D001921:Brain / Q000502:physiology; D003071:Cognition / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography; D064368:Healthy Volunteers; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007858:Learning / Q000187:drug effects*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009538:Nicotine; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine; D012601:Scopolamine
keywords: clinical trials; drug development; neuropharmacology; pharmacotherapy