Abstract
RationaleNicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes.ObjectivesIn this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity.MethodsN=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order.ResultsReaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results.ConclusionsOverall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.
Highlights
Nicotine is a non-selective agonist of the nicotinic acetylcholine receptors that stimulate dopamine release in the nucleus accumbens through activation of dopamine neurons in ventral tegmental area (VTA; Bonci et al 2003; Cachope et al 2012; de Kloet et al 2015; Nisell et al 1994; Threlfell et al 2012; Wonnacott et al 2005)
To explain variability in nicotine response, we focus on a 40-base pair variable number of tandem repeats (VNTR) polymorphism in the 3’ untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT)
Studies examining nicotine effects on cognitive, motor and affective functioning in healthy nonsmokers yield heterogenous results suggesting substantial between-subject variance, possibly related to genetic variations. This preregistered study focused on a candidate polymorphism in a gene related to dopaminergic functioning, the SLC6A3 3’ UTR VNTR. 194 participants were grouped according to genotype and received either nicotine or placebo in a randomized 2×2-between-subjects design
Summary
Nicotine is a non-selective agonist of the nicotinic acetylcholine receptors (nAChr; de Kloet et al 2015; Wonnacott et al 2005) that stimulate dopamine release in the nucleus accumbens (and striatum in general) through activation of dopamine neurons in ventral tegmental area (VTA; Bonci et al 2003; Cachope et al 2012; de Kloet et al 2015; Nisell et al 1994; Threlfell et al 2012; Wonnacott et al 2005).Nicotine has been widely studied for its potential procognitive effects (Hahn 2015; Heishman et al 2010), especially in groups with attentional dysfunction such as patients with neurodegenerative diseases, schizophrenia and ADHD (Barr et al 2008b; Barreto et al 2014; D’Souza and Markou, 2012; Levin et al 1996; Rezvani1 3 Vol.:(0123456789)Psychopharmacology and Levin 2001). Nicotine effects on cognitive performance in healthy individuals are heterogeneous, with some studies providing evidence for beneficial effects, in the domain of attention, yet others suggest detrimental effects (Almeida et al 2020; Ettinger et al 2017; Hahn 2015; Heishman et al 2010; Niemegeers et al 2014; Wignall and de Wit 2011). Nicotine effects appear to depend on factors such as baseline performance, dosage and smoking status (Almeida et al 2020; Niemegeers et al 2014; Wignall and de Wit 2011), suggesting substantial interindividual variance in dopamine-related function. DAT density is high in striatum, a structure known to play a crucial role in dopamine response to nicotine (Cachope et al 2012; Piccini 2003; Threlfell et al 2012)
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