Abstract
RationaleCognitive benefits of nicotinic acetylcholine receptor (nAChR) agonists are well established but have generally been of small magnitude and uncertain clinical significance. A way of raising the effect size may be to facilitate agonist-induced responses by co-administering a nAChR positive allosteric modulator (PAM).ObjectiveThe aim was to test whether galantamine, a PAM at several nAChR subtypes, can potentiate the cognitive-enhancing effects of nicotine.MethodsTwenty-six adult never-smokers were treated, in a double-blind counterbalanced sequence, with nicotine (7 mg/24 h, transdermally) and galantamine (4 mg, p.o.) combined, nicotine alone, galantamine alone, and double placebo. A low dose of galantamine was chosen to minimize acetylcholinesterase inhibition, which was verified in blood assays. In each condition, participants were tested with three cognitive tasks.ResultsNicotine significantly improved reaction time (RT) and signal detection in a visuospatial attention task and the Rapid Visual Information Processing Task. Galantamine did not modulate these effects. A trend toward RT reduction by galantamine correlated with acetylcholinesterase inhibition. In a change detection task, there were no effects of nicotine or galantamine alone on accuracy or RT. However, both drugs combined acted synergistically to reduce RT. This effect was not associated with acetylcholinesterase inhibition.ConclusionsA pattern consistent with allosteric potentiation of nicotine effects by galantamine was observed on one of six performance measures. This may reflect specific nAChR subtype involvement, or additional pharmacological actions of galantamine may have overshadowed similar interactions on other measures. The finding suggests that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle.
Highlights
Several disease states marked by cognitive deficits, most prominently schizophrenia and Alzheimer’s disease, involve nicotinic acetylcholine receptor hypofunction (Adams and Stevens 2007; Hong et al 2011; Kendziorra et al 2011; Perry et al 2000; Petrovsky et al 2010; Wing et al 2012) and may benefit from treatments that enhance nAChR activity (Levin and Rezvani 2002; Singh et al 2004)
The effects of nicotine on weakness/fatigue interacted with time [F(1,26) = 3.64, P = 0.016]: weakness/fatigue increased with cognitive testing, and nicotine appeared to alleviate this increase (Fig. 3b)
The purpose of the present proof-of-concept study was to test whether a nAChR positive allosteric modulator (PAM) could in principle augment the performance-enhancing effects of a nAChR agonist, Fig. 8 Effects of nicotine and galantamine on reaction time in the Change Detection Task, averaged over set sizes 1 and 5
Summary
Several disease states marked by cognitive deficits, most prominently schizophrenia and Alzheimer’s disease, involve nicotinic acetylcholine receptor (nAChR) hypofunction (Adams and Stevens 2007; Hong et al 2011; Kendziorra et al 2011; Perry et al 2000; Petrovsky et al 2010; Wing et al 2012) and may benefit from treatments that enhance nAChR activity (Levin and Rezvani 2002; Singh et al 2004). Drug development efforts have been invested into subtypeselective nAChR agonists for the above conditions. Effects with both α4β2- and α7-selective nAChR agonists have generally been in the expected direction, but tend to be of small magnitude and uncertain clinical significance (Haydar and Dunlop 2010; Radek et al 2010; Wallace et al 2011). Not all (Gronlien et al 2007), PAMs reverse desensitization of a fraction of nAChRs, in the presence of low to intermediate agonist concentrations (Williams et al 2011). Through partial reversal of desensitization or other mechanisms, combined PAM and low-dose agonist treatment may enhance nAChR activity and associated behavioral effects to a greater degree than agonist treatment alone. Dual administration studies performed in people with schizophrenia (Choueiry et al 2019; Deutsch et al 2013) were not designed to differentiate between the effects of the PAM, the agonist, or their combination
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