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

Abstract

Aims: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.

Methods: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.

Results: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and β power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine.

Conclusions: Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.

Keywords: clinical pharmacology; cognitive impairment reversal; healthy subjects; mecamylamine; neuropharmacology; nicotine; pharmacodynamic effects.

Figure 1

Effect on tests evaluating fine coordination, reaction time, attention and alertness.Mecamylamine, nicotine and galantamine effect vs. time during the adaptive tracking test (A), reaction time during the 2‐back condition (B) and visual analogue scale evaluating alertness (C). Symbols represent the mean per treatment group and the polygon (shaded area around the mean) the standard error. Asterisks represent significance between groups (P value is mentioned per overall effect and per group, when applicable). Vertical discontinuous line represents time point zero

Figure 2

Effect on tests evaluating short and long‐term retrieval. Mecamylamine, nicotine and galantamine effect vs. time during the 0‐back condition ratio of correct–incorrect answers (A). Symbols represent the mean per treatment group and the polygon (shaded area around the mean) the standard error. Asterisks represent significance between groups (P value is mentioned per overall effect and per group, when applicable). Vertical discontinuous line represents time point zero. Asterisks represent significance between groups (P value is mentioned per treatment and per group, when applicable). Mecamylamine, nicotine and galantamine effect per treatment group during the delayed word recognition condition of the verbal visual learning test number of correct answers during the (B). The box plots represent the first and third quartile, the middle line the group mean and the vertical lines the confidence interval. Individual observations are plotted as well

Figure 3

Effect on the electroencephalogram. Mecamylamine, nicotine and galantamine effect vs. time for the electroencephalogram Pz‐Oz α (A) and Pz‐Oz β (B) frequency. Symbols represent the mean per treatment group and the polygon the standard error around the mean. Asterisks represent significance between groups (P value is mentioned per treatment and per group, when applicable). The vertical discontinuous line represents time point zero