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

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

doi:10.1111/bcp.13268

Cited by 17 publications

(24 citation statements)

References 66 publications

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“…In a previous exploratory study, we confirmed that administration of 10 and 20 mg of mecamylamine in healthy subjects led to a temporary, dose‐dependent disturbance of several cognitive functions including fine motor coordination and fluency, short‐ and long‐term memory, attention, and concentration . In this study we further investigated the dose–effect relationship of mecamylamine with a higher dose of 30 mg.…”

Section: Introductionmentioning

confidence: 99%

Reversal of mecamylamine‐induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses

Álvarez-Jiménez

Hart

Prins

et al. 2018

Brit J Clinical Pharma

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Section: Introductionmentioning

confidence: 99%

Reversal of mecamylamine‐induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses

Álvarez-Jiménez

Hart

Prins

et al. 2018

Brit J Clinical Pharma

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“…The protocol described in this paper is part of a larger study described in published literature 29,30 and an in press published paper. The results described below are an example of the results of two computerized battery tests, in 12 healthy young male subjects, in a four-way cross-over design.…”

Section: Representative Resultsmentioning

confidence: 99%

“…Since scopolamine is used as a muscarinic acetylcholine challenge model to induce Alzheimer-like, yet temporary, cognitive effect in healthy subjects 27 , CHDR has developed and validated a pharmacological challenge model with mecamylamine. Mecamylamine is a non-competitive nicotinic acetylcholine receptor antagonist 28 which results in cholinergic dysfunction, i.e., transient cognitive deficits, in healthy young males 29,30 .…”

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confidence: 99%

“…The grey circles represent actual data points (i.e., observations). This figure has been modified from Baakman et al 30 Please click here to view a larger version of this figure.…”

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confidence: 99%

“…The percentage of correctly tracked is presented on the y-axis, time-point post-dose is presented on x-axis, with double placebo (oral and intravenous) results (grey circle), 10 mg mecamylamine results (magenta square), 20 mg mecamylamine results (green triangles) and 0.5 mg scopolamine (blue diamonds). This figure has been modified from Baakman et al30 Please click here to view a larger version of this figure.…”

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A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development

Hart

Álvarez-Jiménez

Davidse

et al. 2019

JoVE

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Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug. The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors. Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders. A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs. Video Link The video component of this article can be found at https://www.jove.com/video/56569/ 3. Also, outcomes of the test battery could provide information on the mechanism of action of a compound as the individual tests correspond to specific drug-responsive CNS domains. For example, if effects of the new drug are seen on the maze learning test, which is a test for visuospatial working memory, this could indicate that the drug acts on receptors in parts of the brain

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Estradiol treatment in young postmenopausal women with self‐reported cognitive complaints: Effects on cholinergic‐mediated cognitive performance

Conley

Albert

McDonald

et al. 2022

Human Psychopharmacology

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Objective: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment.However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated.This study investigated the effect of estrogen treatment using 17β-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints.Methods: Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC).Results: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. Conclusions:The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.

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

Cited by 17 publications

References 66 publications

Reversal of mecamylamine‐induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses

Reversal of mecamylamine‐induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses

A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development

Estradiol treatment in young postmenopausal women with self‐reported cognitive complaints: Effects on cholinergic‐mediated cognitive performance

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