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Cortical excitability in smoking and not smoking individuals with and without nicotine

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rational

Activation of nicotinic acetylcholine receptors has a major neuromodulatory impact on central nervous system function. Beyond acute activation, chronic nicotine intake has long-lasting effects on cortical excitability in animal experiments, caused by receptor up- or down-regulation. Knowledge about the impact of nicotine on cortical excitability in humans, however, is limited.

Objectives

We therefore aimed to explore the effect of nicotine intake on cortical excitability in healthy human smokers and non-smokers.

Methods

The primary motor cortex served as model, and cortical excitability was monitored via transcranial magnetic stimulation (TMS). Corticospinal excitability and intracortical excitability were recorded before and after application of nicotine patch in both groups. Corticospinal excitability was explored by motor threshold and input/output curve (I/O curve), and intracortical excitability was explored by means of paired-pulse TMS techniques (intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), I-wave facilitation and short-latency afferent inhibition (SAI)).

Results

The results show that smokers during nicotine withdrawal display increased corticospinal excitability with regard to the I/O curve (TMS intensity 150 % of resting motor threshold) compared to non-smokers and furthermore enhanced SAI and diminished ICF at the intracortical circuit level. After administration of nicotine, intracortical facilitation in smokers increased, while in non-smokers, inhibition (SICI, SAI) was enhanced.

Conclusion

Our results show that chronic nicotine consumption in smokers alters cortical excitability independent from acute nicotine consumption and that acute nicotine has different effects on motor cortical excitability in both groups.

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Abbreviations

ADM:

Abductor digiti minimi muscle

AMT:

Active motor threshold

ICF:

Intracortical facilitation

I/O curves:

Input/output curves

ISI:

Interstimulus interval

MEP:

Motor evoked potential

nAChR:

Nicotinic acetylcholine receptors

RMT:

Resting motor threshold

S1mV:

TMS intensity needed to elicit an MEP of 1 mV

SAI:

Short-interval afferent inhibition

SICI:

Short-latency intracortical inhibition

TMS:

Transcranial magnetic stimulation

References

  • Alkandon M, Braga MF, Pereira EF, Maelicke A, Albuquerque EX (2000) Alpha7 nicotinic acetylcholine receptors and modulation of gabaergic synaptic transmission in the hippocampus. Eur J Pharmacol 393:59–67

    Article  Google Scholar 

  • Barone JA (1999) Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother 33(4):429–440, Review

    Article  PubMed  CAS  Google Scholar 

  • Burnashev N (1998) Calcium permeability of ligand-gated channels. Cell Calcium 24(5–6):325–332, Review

    Article  PubMed  CAS  Google Scholar 

  • Chen R (2000) Studies of human motor physiology with transcranial magnetic stimulation. Muscle Nerve Suppl (9):S26–32

  • Chevallier S, Nagy F, Cabelguen JM (2006) Cholinergic control of excitability of spinal motoneurones in the salamander. J Physiol 570(Pt 3):525–540

    Article  PubMed  CAS  Google Scholar 

  • Cole DM, Beckmann CF, Long CJ, Matthews PM, Durcan MJ, Beaver JD (2010) Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics. NeuroImage 52(2):590–599

    Article  PubMed  CAS  Google Scholar 

  • Cordero-Erausquin M, Marubio LM, Klink R, Changeux JP (2000) Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol Sci 21(6):211–217

    Article  PubMed  CAS  Google Scholar 

  • Di Lazzaro V, Oliviero A, Profice P, Saturno E, Pilato F, Insola A, Mazzone P, Tonali P, Rothwell JC (1998) Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroencephalogr Clin Neurophysiol 109(5):397–401

    Article  PubMed  Google Scholar 

  • Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Di Giovanni S, Zito G, Tonali P, Rothwell JC (2000) Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res 135:455–461

    Article  PubMed  Google Scholar 

  • Di Lazzaro V, Pilato F, Dileone M, Tonali MA, Ziemann U (2005) Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition. J Physiol 569:315–323

    Article  PubMed  Google Scholar 

  • Di Lazzaro V, Pilato F, Dileone M, Saturno E, Oliviero A, Marra C, Daniele A, Ranieri F, Gainotti G, Tonali PA (2006) In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. Neurology 66(7):1111–1113

    Google Scholar 

  • Di Lazzaro V, Pilato F, Dileone M, Profice P, Ranieri F, Ricci V, Bria P, Tonali PA, Ziemann U (2007) Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study. Clin Neurophysiol 118(10):2207–2214

    Article  PubMed  Google Scholar 

  • Even N, Cardona A, Soudant M, Corringer PJ, Changeux JP, Cloëz-Tayarani I (2008) Regional differential effects of chronic nicotine on brain alpha 4-containing and alpha 6-containing receptors. Neuroreport 19:1545–1550

    Article  PubMed  CAS  Google Scholar 

  • Fenster CP, Rains MF, Noerager B, Quick MW, Lester RA (1997) Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine. J Neurosci 17(15):5747–5759

    PubMed  CAS  Google Scholar 

  • Fiore MC, Smith SS, Jorenby DE, Baker TB (1994) The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 271(24):1940–1947

    Article  PubMed  CAS  Google Scholar 

  • Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A, Feredoes E, Marcolin MA, Rigonatti SP, Silva MT, Paulus W, Pascual-Leone A (2005) Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res 166(1):23–30

    Article  PubMed  Google Scholar 

  • Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158(9):1367–1377, Review

    Article  PubMed  CAS  Google Scholar 

  • Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA (1996) Hippocampal synaptic transmission enhanced by low concentration of nicotine. Nature 383:713–716

    Article  PubMed  CAS  Google Scholar 

  • Hahn B, Shoaib M, Stolerman IP (2002) Nicotine-induced enhancement of attention in the five-choice serial reaction time task, the influence of task demand. Psychopharmacology 162:129–137

    Article  PubMed  CAS  Google Scholar 

  • Hogg RC, Raggenbass M, Bertrand D (2003) Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol 147:1–46, Epub 2003 Mar 20. Review

    Article  PubMed  CAS  Google Scholar 

  • Hosur V, Leppanen S, Abutaha A, Loring RH (2009) Gene regulation of alpha4beta2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effects. J Neurochem 111(3):848–5

    Article  PubMed  CAS  Google Scholar 

  • Ilić TV, Meintzschel F, Cleff U, Ruge D, Kessler KR, Ziemann U (2002) Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545(Pt 1):153–167

    PubMed  Google Scholar 

  • Jakobsen LK, Krystal JH, Mencl WE, Westerveld M, Frost SJ, Pugh KR (2005) Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers. Psychiatry 57:56–66

    Google Scholar 

  • Kawa K (2007) Inhibitory synaptic transmission in area postrema neurons of the rat showing robust presynaptic facilitation mediated by nicotinic ACh receptors. Brain Res 1130(1):83–94

    Article  PubMed  CAS  Google Scholar 

  • Kleykamp BA, Jennings JM, Eissenberg T (2011) Effects of transdermal nicotine and concurrent smoking on cognitive performance in tobacco-abstinent smokers. Exp Clin Psychopharmacol 19(1):75–84

    Article  PubMed  Google Scholar 

  • Korchounov A, Ilic TV, Schwinge T, Ziemann U (2005) Modification of motor cortical excitability by an acetylcholinesterase inhibitor. Exp Brain Res 164:399–405

    Article  PubMed  CAS  Google Scholar 

  • Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519

    PubMed  CAS  Google Scholar 

  • Kumari V, Gray JA, ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E, Vythelingum GN, Williams SC, Simmons A, Sharma T (2003) Cognitive effects of nicotine in humans: an fMRI study. NeuroImage 19:1002–1012

    Article  PubMed  Google Scholar 

  • Lang N, Hasan A, Sueske E, Paulus W, Nitsche MA (2008) Cortical hypoexcitability in chronic smokers? A transkranial magnetic stimulation study. Neuropsychopharmacology 33:2517–2523

    Article  PubMed  CAS  Google Scholar 

  • Lang N, Rothkegel H, Reiber H, Hasan A, Sueske E, Tergau F, Ehrenreich H, Wuttke W, Paulus W (2011) Circadian modulation of GABA-mediated cortical inhibition. Cereb Cortex 21(10):2299–2306

    Article  PubMed  Google Scholar 

  • Le Novère N, Corringer PJ, Changeux JP (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53(4):447–456, Review

    Article  PubMed  Google Scholar 

  • Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioural characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523–539, Review

    Article  CAS  Google Scholar 

  • Mansvelder HD, van Aerde KI, Couey JJ, Brussaard AB (2006) Nicotinic modulation of neuronal networks: from receptors to cognition. Psychopharmacology (Berl) 184(3–4):292–305, Review

    Article  CAS  Google Scholar 

  • Mansvelder HD, Mertz M, Role LW (2009) Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits. Semin Cell Dev Biol 20(4):432–440

    Article  PubMed  CAS  Google Scholar 

  • Miura M, Ishii K, Asoki T, Sumikawa K (2006) Chronic nicotine treatment increases GABA-ergic input to striatal neurons. Neuroreport 17:537–540

    Article  PubMed  CAS  Google Scholar 

  • Orth M, Münchau A, Rothwell JC (2008) Corticospinal system excitability at rest is associated with tic severity in Tourette syndrome. Biol Psychiatry 64(3):248–251

    Article  PubMed  Google Scholar 

  • Parish CL, Nunan J, Finkelstein DI, McNamara FN, Wong JY, Waddington JL, Brown RM, Lawrence AJ, Horne MK, Drago J (2005) Mice lacking the alpha4 nicotinic receptor subunit fail to modulate dopaminergic neuronal arbors and possess impaired dopamine transporter function. Mol Pharmacol 68(5):1376–1386

    Article  PubMed  CAS  Google Scholar 

  • Potter AS, Newhouse PA (2008) Acute nicotine improves cognitive deficits in young adults with attention-deficit/hyperactivity disorder. Pharmacol Biochem Behav 88:407–417

    Article  PubMed  CAS  Google Scholar 

  • Ridding MC, Rothwell JC (1997) Stimulus/response curves as a method of measuring motor cortex excitability in man. Electroencephalogr Clin Neurophysiol 105:340–344

    Article  PubMed  CAS  Google Scholar 

  • Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W (1999) Magnetic stimulation: motor evoked potentials. Int Fed Clin Neuropysiology Electroencephalogr Clin Neurophysiol Suppl 52:97–103

    CAS  Google Scholar 

  • Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, Jatlow PI, Wexler BE, George TP (2005) Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry 62:649–659

    Article  PubMed  Google Scholar 

  • Schwartz RD, Kellar KJ (1983) Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science 220(4593):214–216

    Article  PubMed  CAS  Google Scholar 

  • Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R, Zenz M, Malin JP, Tegenthoff M (1999) Influence of the N-methyl-d-aspartate antagonist memantine on human motor cortex excitability. Neurosci Lett 270(3):137–140

    Article  PubMed  CAS  Google Scholar 

  • Spirt MJ, Chan W, Thieberg M, Sachar DB (1992) Neuroleptic malignant syndrome induced by domperidone. Dig Dis Sci 37(6):946–948

    Article  PubMed  CAS  Google Scholar 

  • Strenge H, Schmidt G, Niederberger U, Porschke H, Schütz HW (1996) Effects of nicotine gum on F waves in non-smokers. Funct Neurol 11(4):179–185

    Google Scholar 

  • Thiel CM, Zilles K, Fink GR (2005) Nicotine modulates reorienting of visuospatial attention and neural activity in human parietal cortex. Neuropsychopharmacology 30:810–820

    PubMed  CAS  Google Scholar 

  • Turner TJ (2004) Nicotine enhancement of dopamine release by a calcium-dependent increase in the size of the readily releasable pool of synaptic vesicles. J Neurosci 24(50):11328–11336

    Article  PubMed  CAS  Google Scholar 

  • Wall A, Gong ZH, Johnson AE, Meyerson B, Zhang X (2000) Cross-tolerance in drug, response and differential changes in central nicotinic and N-methyl-d-aspartate receptor binding following chronic treatment with either (+)- or (−)-nicotine. Psychopharmacology 148:186–195

    Article  PubMed  CAS  Google Scholar 

  • Wang BW, Liao WN, Chang CT, Wang SJ (2006) Facilitation of glutamate release by nicotine involves the activation of a Ca2+/calmodulin signaling pathway in rat prefrontal cortex nerve terminals. Synapse 59(8):491–501

    Article  PubMed  CAS  Google Scholar 

  • Wang F, Chen H, Steketee JD, Sharp BM (2007) Upregulation of ionotropic glutamate receptor subunits within specific mesocorticolimbic regions during chronic nicotine self-administration. Neuropsychopharmacology 32(1):103–109

    Article  PubMed  CAS  Google Scholar 

  • Ziemann U (2004) TMS induced plasticity in human cortex. Rev Neurosci 15(4):253–266

    Google Scholar 

  • Ziemann U, Lönnecker S, Paulus W (1995) Inhibition of human motor cortex by ethanol. A transcranial magnetic stimulation study. Brain 118:1437–1446

    Article  PubMed  Google Scholar 

  • Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus W (1998a) Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation. J Physiol 511:181–190

    Article  PubMed  CAS  Google Scholar 

  • Ziemann U, Chen R, Cohen LG, Hallett M (1998b) Dextromethorphan decreases the excitability of the human motor cortex. Neurology 51(5):1320–1324

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG grant NI683/4-1 ‘Towards risk prediction of nicotine dependency by exploring individual limits of cortical neuroplasticity in humans’ and ‘Impact of the nicotinergic alpha7 receptor on cortical plasticity in smokers and non-smokers’) within the DFG priority program ‘Nicotine: Molecular and Physiological Effects in Central Nervous System’.

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Authors and Affiliations

  1. Department of Clinical Neurophysiology, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    J. Grundey, S. Freznosa, F. Klinker, W. Paulus & M. A. Nitsche

  2. Department of Neurology, University of Kiel, Kiel, Germany

    N. Lang

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  1. J. Grundey
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  2. S. Freznosa
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  3. F. Klinker
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  4. N. Lang
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  5. W. Paulus
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  6. M. A. Nitsche
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Corresponding author

Correspondence to J. Grundey.

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Table S 1

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Table S 2

(DOC 82 kb)

Figure Online Resource 2

Displays the I/O curve for 10 healthy non-smoking subjects at baseline, 2 hours after administration of 20 mg domperidone and again 4 hours after administration of a second dosage domperidone (6 hours post, relating to baseline). Shown are the graphs with the standardized MEP-amplitudes (y-axis) plotted against the respective stimulation intensity (x-axis). Hereby RMT signifies resting motor threshhold. There is no significant difference between the MEP-amplitudes at baseline and the MEP-amplitudes 2 and 6 hours after baseline measurements and domperidone ingestion (Students t-test, paired, two-tailed, p < 0.05). Error bars indicate standard error of mean. (PPT 137 kb)

Figure Online Resource 3

Displays MEP-amplitudes at different timepoints. TMS intensity was determined to elicit an MEP of about 1 mV at baseline and kept constant throughout the experiment. Shown are the graphs with motor-evoked potential (MEP) on the y-axis at different timepoints after administration of domperidone (x-axis). There is no significant difference between the MEP-amplitude before and after administration of domperidone (2 hours and 6 hours) (Students t-test, paired, two-tailed, p < 0.05). Error bars indicate standard error of mean. (PPT 108 kb)

Figure Online Resource 4

Displays short latency afferent inhibition (SAI) at an interstimulus interval of 20 ms for 6 healthy non-smokers at baseline, 2 hours after administration of 20 mg domperidone and again 4 hours after administration of a second dosage domperidone (6 hours post, relating to baseline). Shown are the graphs with the standardized MEP-amplitude (y-axis) plotted against the timepoints (x-axis; baseline, 2 hours post, 6 hours post). There is no significant difference between the MEP-amplitude at baseline and the MEP-amplitude 2 and 6 hours after baseline measurements and domperidone ingestion (Students t-test, paired, two-tailed, p < 0.05). Error bars indicate standard error of mean. (PPT 114 kb)

Figure Online Resource 5

Displays short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) of 10 healthy non-smoking subjects at baseline, 2 hours after administration of 20 mg domperidone and again 4 hours after administration of a second dosage domperidone (6 hours post, relating to baseline). Shown are the graphs with the standardized MEP-amplitudes (y-axis) plotted against the respective interstimulus intervals ( x-axis; 2 ms, 3 ms, 7 ms, 10 ms, 15 ms). There is no significant difference between the MEP-amplitudes at baseline and the MEP-amplitudes 2 and 6 hours after baseline measurements and domperidone ingestion (Students t-test, paired, two-tailed, p < 0.05). Error bars indicate standard error of mean. (PPT 137 kb)

Figure Online Resource 6

Displays the i-wave facilitation of 6 healthy non-smoking subjects at different interstimulus intervals (ISIs) at baseline, 2 hours after administration of 20 mg domperidone and again 4 hours after administration of a second dosage domperidone (6 hours post, relating to baseline). Shown are the graphs with the standardized MEP-amplitudes (y-axis) plotted against the respective interstimulus intervals (x-axis). There is no significant difference between the MEP-amplitudes at baseline and the MEP-amplitudes 2 and 6 hours after baseline measurements and domperidone ingestion (Students t-test, paired, two-tailed, p < 0.05). Error bars indicate standard error of mean. (PPT 150 kb)

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Grundey, J., Freznosa, S., Klinker, F. et al. Cortical excitability in smoking and not smoking individuals with and without nicotine. Psychopharmacology 229, 653–664 (2013). https://doi.org/10.1007/s00213-013-3125-6

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  • DOI: https://doi.org/10.1007/s00213-013-3125-6

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