An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine

Anne Catrien Baakman, Ricardo Alvarez-Jimenez, Robert Rissmann, Erica S. Klaassen, Jasper Stevens, Sebastiaan C. Goulooze, Jeroen C.G. den Burger, Eleonora L. Swart, Joop M.A. van Gerven, Geert Jan Groeneveld

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims: 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. Methods: 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. Results: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml−1 for 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1676-1687
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume83
Issue number8
DOIs
Publication statusPublished - 2017

Cite this

Baakman, A. C., Alvarez-Jimenez, R., Rissmann, R., Klaassen, E. S., Stevens, J., Goulooze, S. C., ... Groeneveld, G. J. (2017). An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine. British Journal of Clinical Pharmacology, 83(8), 1676-1687. https://doi.org/10.1111/bcp.13268
Baakman, Anne Catrien ; Alvarez-Jimenez, Ricardo ; Rissmann, Robert ; Klaassen, Erica S. ; Stevens, Jasper ; Goulooze, Sebastiaan C. ; den Burger, Jeroen C.G. ; Swart, Eleonora L. ; van Gerven, Joop M.A. ; Groeneveld, Geert Jan. / An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine. In: British Journal of Clinical Pharmacology. 2017 ; Vol. 83, No. 8. pp. 1676-1687.
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title = "An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine",
abstract = "Aims: 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. Methods: 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. Results: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml−1 for 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. Conclusion: 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.",
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author = "Baakman, {Anne Catrien} and Ricardo Alvarez-Jimenez and Robert Rissmann and Klaassen, {Erica S.} and Jasper Stevens and Goulooze, {Sebastiaan C.} and {den Burger}, {Jeroen C.G.} and Swart, {Eleonora L.} and {van Gerven}, {Joop M.A.} and Groeneveld, {Geert Jan}",
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Baakman, AC, Alvarez-Jimenez, R, Rissmann, R, Klaassen, ES, Stevens, J, Goulooze, SC, den Burger, JCG, Swart, EL, van Gerven, JMA & Groeneveld, GJ 2017, 'An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine' British Journal of Clinical Pharmacology, vol. 83, no. 8, pp. 1676-1687. https://doi.org/10.1111/bcp.13268

An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine. / Baakman, Anne Catrien; Alvarez-Jimenez, Ricardo; Rissmann, Robert; Klaassen, Erica S.; Stevens, Jasper; Goulooze, Sebastiaan C.; den Burger, Jeroen C.G.; Swart, Eleonora L.; van Gerven, Joop M.A.; Groeneveld, Geert Jan.

In: British Journal of Clinical Pharmacology, Vol. 83, No. 8, 2017, p. 1676-1687.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine

AU - Baakman, Anne Catrien

AU - Alvarez-Jimenez, Ricardo

AU - Rissmann, Robert

AU - Klaassen, Erica S.

AU - Stevens, Jasper

AU - Goulooze, Sebastiaan C.

AU - den Burger, Jeroen C.G.

AU - Swart, Eleonora L.

AU - van Gerven, Joop M.A.

AU - Groeneveld, Geert Jan

PY - 2017

Y1 - 2017

N2 - Aims: 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. Methods: 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. Results: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml−1 for 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. Conclusion: 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.

AB - Aims: 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. Methods: 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. Results: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml−1 for 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. Conclusion: 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.

KW - clinical trials

KW - drug development

KW - neuropharmacology

KW - pharmacotherapy

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U2 - 10.1111/bcp.13268

DO - 10.1111/bcp.13268

M3 - Article

VL - 83

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JF - British Journal of Clinical Pharmacology

SN - 0306-5251

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