Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic α4β2-receptor partial agonist varenicline

Abstract

Nicotine modulates neuroplasticity and improves cognitive functions in animals and humans. In the brain of smoking individuals, calcium-dependent plasticity induced by non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) is impaired by nicotine withdrawal, but partially re-established after nicotine re-administration. In order to investigate the underlying mechanism further, we tested the impact of the α₄β₂-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity in smokers during nicotine withdrawal, induced by PAS and tDCS, respectively. We administered low (0.3 mg) and high (1.0 mg) single doses of varenicline or placebo medication before stimulation over the left motor cortex of 20 healthy smokers under nicotine withdrawal. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes for 36 hours after plasticity induction. Stimulation-induced plasticity was absent under placebo medication, whereas it was present in all conditions under high dose. Low dose restituted only tDCS-induced non-focal plasticity, producing no significant impact on focal plasticity. High dose varenicline also prolonged inhibitory plasticity. These results are comparable to the impact of nicotine on withdrawal-related impaired plasticity in smokers and suggest that α₄β₂ nicotinic receptors are relevantly involved in plasticity deficits and restitution in smokers.

Figure 1

Course of the study. Participants were not allowed to smoke 10 h before and during the experimental session. In the beginning of each session, 25 baseline single pulse MEPs were recorded at an intensity to elicit MEPs with peak-to-peak amplitudes of on average ~1 mV before administration of varenicline (0.3 or 1 mg) or placebo medication. Three hours later, a second baseline was recorded to explore the effect of medication on cortical excitability, and the stimulation intensity was adjusted, if necessary (third baseline). Next, tDCS (cathodal or anodal) or PAS (PAS10 or PAS25) was administered and blocks of 25 MEPs were recorded at time points of 0, 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after plasticity induction. Further TMS measurements were conducted in the evening of the same day (SE), morning (at ~9:00 AM, NM), noon (at ~12:00 PM, NN) and evening (at ~6:00 PM, NE) of the second day.

Figure 2

Impact of varenicline on tDCS-induced neuroplasticity. Shown are baseline-normalized MEP amplitudes after plasticity induction by anodal (A) and cathodal (B) tDCS under 0.3 mg, 1.0 mg varenicline or placebo medication conditions up to the evening of the post-stimulation day. (A) In smokers under placebo medication, anodal tDCS induced no excitability enhancement, while 0.3 mg and 1.0 mg varenicline resulted in enhanced MEP amplitudes after anodal tDCS. (B) In the placebo condition, cathodal tDCS failed to induce excitability alterations. In contrast, both low and high doses of varenicline led to significant inhibitory after-effects of tDCS. Error bars indicate S.E.M. Filled symbols indicate significant differences of post-stimulation MEP amplitudes from respective baseline values; Floating symbols indicate significant differences between the respective drug and placebo medication conditions at the same time points (Student’s t-test, two tailed, paired samples, p < 0.05).

Figure 3

In smokers under placebo medication, tDCS- and PAS-induced plasticity is abolished. Furthermore, PAS also induced no excitability alterations under 0.3 mg varenicline. High dose varenicline restituted both tDCS and PAS-induced after-effects, while 0.3 mg varenicline only restored tDCS-induced plasticity. Each column represents the mean of baseline-normalized MEP ± S.E.M. amplitudes until 30 minutes after stimulation; Asterisks indicate significant differences between drug and placebo conditions (Student’s t-test, two tailed, paired samples, p < 0.05).

Figure 4

Impact of varenicline on PAS-induced neuroplasticity. Shown are baseline-normalized MEP amplitudes after plasticity induction by PAS25 (A) and PAS10 (B) under 0.3 mg, 1.0 mg varenicline or placebo medication conditions up to the evening of the post-stimulation day. Both, PAS25 and PAS10 induce no changes of MEP amplitudes in smokers under placebo or 0.3 mg varenicline conditions. (A) Cortical excitability was significantly enhanced for up to 30 minutes under high dose varenicline after PAS25 administration. (B) High dose varenicline restored inhibitory plasticity after PAS10. Error bars indicate S.E.M. Filled symbols indicate significant differences of post-stimulation MEP amplitudes from respective baseline values; floating symbols indicate significant differences between the respective drug and placebo medication conditions at the same time points (Student’s t-test, two tailed, paired samples, p < 0.05).