The role of the SLC6A3 3' UTR VNTR in nicotine effects on cognitive, affective, and motor function

Abstract

Rationale: Nicotine 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.

Objectives: In 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.

Methods: N=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.

Results: Reaction 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.

Conclusions: Overall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.

Keywords: DAT; Individual differences; Inhibition; Nicotine; Proactive inhibition; SLC6A3; Smooth pursuit; Spontaneous blink rate; Stop signal task.

Fig. 1

Study procedure. M.I.N.I: Mini International Neuropsychiatric Interview (Ackenheil et al., 1999), EHI: Edinburgh Handedness Inventory (Oldfield, 1971), MWT-B: Mehrfachwahl-Wortschatz-Intelligenztest, version B (Lehrl, 1999), VAS: visual analogue scales (Bond & Lader, 1974), SBR: spontaneous blink rate, ACP: Anticipatory and Consummatory Pleasure Task.

Fig. 2

Conceptual (panel A) and statistical (panel B) diagram of the conditional process models. Spontaneous blink rate is considered a mediator of the drug effects on the four performance outcomes (smooth pursuit velocity gain, stop signal reaction time, go reaction time and key press speed). For each performance outcome, a separate analysis was carried out. Genotype acts as a moderator of the drug effect on spontaneous blink rate and performance.

Fig. 3

Effects of drug and genotype on spontaneous blink rate. Data are presented as mean ± standard errors. N = 192.

Fig. 4

Effects of drug, genotype, target velocity and background on smooth pursuit velocity gain. Data are presented as mean ± standard errors. N = 187

Fig. 5

Effects of drug and genotype on stop signal reaction time. Data are presented as mean ± standard errors. SSRT: stop signal reaction time. N = 161.

Fig. 6

Effects of drug and genotype on go reaction times in the simple choice and stop signal tasks. Data are presented as mean ± standard errors. RT: reaction time. N = 182.

Fig. 7

Effects of drug and genotype on key press speed in the ACP task. Data are presented as mean ± standard errors. N = 191.