Skip to main content
SpringerLink
Log in

A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia

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

Abstract

Rationale

Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans.

Objectives

To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI.

Materials and methods

In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 μg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1.

Results

Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups.

Conclusions

Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abel K, Waikar M, Pedro B, Hemsley D, Geyer M (1998) Repeated testing of prepulse inhibition and habituation of the startle reflex: a study in healthy human controls. J Psychopharmacol 12(4):330–337

    Article  PubMed  CAS  Google Scholar 

  • Acri JB, Grunberg NE, Morse DE (1991) Effects of nicotine on the acoustic startle reflex amplitude in rats. Psychopharmacology 104(2):244–248

    Article  PubMed  CAS  Google Scholar 

  • Acri JB, Morse DE, Popke EJ, Grunberg NE (1994) Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats. Psychopharmacology 114(2):369–374

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R (1992) Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry 32(7):607–616

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Hoffer LD, Wise A, Freedman R (1993) Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150(12):1856–1861

    PubMed  CAS  Google Scholar 

  • Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R (1998) Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull 24:189–202

    PubMed  CAS  Google Scholar 

  • Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343

    Article  PubMed  CAS  Google Scholar 

  • Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 156(2–3):234–258

    Article  PubMed  CAS  Google Scholar 

  • Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364

    Article  PubMed  CAS  Google Scholar 

  • Bullock AE, Slobe BS, Vázquez V, Collins AC (1997) Inbred mouse strains differ in the regulation of startle and prepulse inhibition of the startle response. Behav Neurosci 111:1353–1360

    Article  PubMed  CAS  Google Scholar 

  • Cadenhead KS, Carasso BS, Swerdlow NR, Geyer MA, Braff DL (1999) Prepulse inhibition and habituation are stable neurological measures in a normal male population. Biol Psychiatry 45:360–364

    Article  PubMed  CAS  Google Scholar 

  • Curzon P, Kim DJ, Decker MW (1994) Effect of nicotine, lobeline, and mecamylamine on sensory gating in the rat. Pharmacol Biochem Behav 49(4):877–882

    Article  PubMed  CAS  Google Scholar 

  • Della Casa V, Hofer I, Weiner I, Feldon J (1998) The effects of smoking on acoustic prepulse inhibition in healthy men and women. Psychopharmacology 137(4):362–368

    Article  PubMed  Google Scholar 

  • de Leon J, Dadvand M, Canuso C, White AO, Stanilla JK, Simpson GM (1995) Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry 152:453–455

    PubMed  Google Scholar 

  • de Leon J, Tracy J, McCann E, McGrory A, Diaz FJ (2002) Schizophrenia and tobacco smoking: a replication study in another US psychiatric hospital. Schizophr Res 56(1–2):55–65

    Article  PubMed  Google Scholar 

  • Diwan A, Castine M, Pomerleau CS, Meador-Woodruff JH, Dalack GW (1998) Differential prevalence of cigarette smoking in patients with schizophrenic vs mood disorders. Schizophr Res 33(1–2):113–118

    Article  PubMed  CAS  Google Scholar 

  • Duncan E, Madonick S, Chakravorty S, Parwani A, Szilagyi S, Efferen T, Gonzenbach S, Angrist B, Rotrosen J (2001) Effects of smoking on acoustic startle and prepulse inhibition in humans. Psychopharmacology 156(2–3):266–272

    Article  PubMed  CAS  Google Scholar 

  • Faraday MM, O’Donoghue VA, Grunberg NE (1999) Effects of nicotine and stress on startle amplitude and sensory gating depend on rat strain and sex. Pharmacol Biochem Behav 2(2):273–284

    Article  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (1995) Structured clinical interview for DSM-IV Axis II disorders, patient edition (SCID-P), version 2. New York State Psychiatric Institute, Biometrics Research, New York

  • First MB, Spitzer RL, Gibbon M, Williams JBW (1996) Structured clinical interview for DSM-IV Axis I disorders, non-patient edition (SCID-1/NP), version 2. New York State Psychiatric Institute, Biometrics Research, New York

  • Fagerstrom KO, Schneider NG (1989) Measuring nicotine dependence: a review of the Fagerstrom tolerance questionnaire. J Behav Med 12:159–182

    Article  PubMed  CAS  Google Scholar 

  • Flaten MA (2002) Test–retest reliability of the somatosensory blink reflex and its inhibition. Int J Psychophysiol 45(3):261–265

    Article  PubMed  Google Scholar 

  • Freedman R, Wetmore C, Stromberg I, Leonard S, Olson L (1993) Alpha-bungarotoxin binding to hippocampal interneurons: immunocytochemical characterization and effects on growth factor expression. J Neurosci 13:1965–1975

    PubMed  CAS  Google Scholar 

  • Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–33

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Ellenbroek B (2003) Animal behavior models of the mechanisms underlying antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27(7):1071–1079

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25:485–498

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156(2–3):117–154

    Article  PubMed  CAS  Google Scholar 

  • Glassman AH (1993) Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 150(4):546–553

    PubMed  CAS  Google Scholar 

  • Graham FK (1975) The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248

    Article  PubMed  CAS  Google Scholar 

  • Hazlett EA, Buchsbaum MS, Haznedar MM, Singer MB, Germans MK, Schnur DB, Jimenez EA, Buchsbaum BR, Troyer BT (1998) Prefrontal cortex glucose metabolism and startle eyeblink modification abnormalities in unmedicated schizophrenia patients. Psychophysiology 35:186–198

    Article  PubMed  CAS  Google Scholar 

  • Hazlett EA, Buchsbaum MS, Tang CY, Fleischman MB, Wei TC, Byne W, Haznedar MM (2001) Thalamic activation during an attention-to-prepulse startle modification paradigm: a functional MRI study. Biol Psychiatry 50(4):281–291

    Article  PubMed  CAS  Google Scholar 

  • Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA (1986) Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 143(8):993–997

    PubMed  CAS  Google Scholar 

  • Jacobsen LK, D’Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH (2004) Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry 55(8):850–858

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148(10):1301–1318

    PubMed  CAS  Google Scholar 

  • Kay SR, Fiszbein PS, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276

    CAS  Google Scholar 

  • Kodsi MH, Swerdlow NR (1995a) Ventral pallidal GABA-A receptors regulate prepulse inhibition of acoustic startle. Brain Res 684:26–35

    Article  PubMed  CAS  Google Scholar 

  • Kodsi MH, Swerdlow NR (1995b) Prepulse inhibition in the rat is regulated by ventral and caudodorsal striato–pallidal circuitry. Behav Neurosci 109:912–928

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Gray JA (1999) Smoking withdrawal, nicotine dependence and prepulse inhibition of the acoustic startle reflex. Psychopharmacology 141:11–15

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Soni W, Mathew VM, Sharma T (2000) Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication. Arch Gen Psychiatry 57:609–614

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Postma P (2005) Nicotine use in schizophrenia: the self-medication hypotheses. Neurosci Biobehav Rev 29(6):1021–1034

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Checkley SA, Gray JA (1996) Effect of cigarette smoking on prepulse inhibition of the acoustic startle reflex in healthy male smokers. Psychopharmacology 128(1):54–60

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Cotter PA, Checkley SA, Gray JA (1997) Effect of acute subcutaneous nicotine on prepulse inhibition of the acoustic startle reflex in healthy male non-smokers. Psychopharmacology 132(4):389–395

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Soni W, Sharma T (2001) Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Hum Psychopharmacol 16:321–326

    Article  PubMed  Google Scholar 

  • Kumari V, Gray JA, Geyer MA, Mitterschiffthaler M, Ffytche D, Vythelingum GN, Soni W, Simmons A, Williams SCR, Sharma T (2003a) Neural correlates of prepulse inhibition in normal and schizophrenic subjects: a functional MRI study. Psychiatry Res Neuroimaging 122:99–113

    Article  Google Scholar 

  • Kumari V, Gray JA, ffytche D, Mitterschiffthaler MT, Das M, Zachariah E, Vythelingum GN, Williams SCR, Simmons A, Sharma T (2003b) Cognitive effects of nicotine in humans: a functional MRI investigation. NeuroImage 19:1002–1013

    Article  PubMed  Google Scholar 

  • Kumari V, Aasen I, Sharma T (2004) Sex effects in prepulse modification deficits in schizophrenia. Schizophr Res 69(2–3):219–235

    Article  PubMed  Google Scholar 

  • Kumari V, Antonova E, Zachariah E, Galea A, Aasen I, Mitterschiffthaler MT, Sharma T (2005) Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans. NeuroImage 26(4):1052–1058

    Article  PubMed  Google Scholar 

  • Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467

    Article  PubMed  CAS  Google Scholar 

  • Leonard S, Adams C, Breese CR, Adler LE, Bickford P, Byerley W, Coon H, Griffith JM, Miller C, Myles-Worsley M, Nagamoto HT, Rollins Y, Stevens KE, Waldo M, Freedman R (1996) Nicotinic receptor function in schizophrenia. Schizophr Bull 22(3):431–445

    PubMed  CAS  Google Scholar 

  • Leonard S, Gault J, Adams C, Breese CR, Rollins Y, Adler LE, Olincy A, Freedman R (1998) Nicotinic receptors, smoking and schizophrenia. Restor Neurol 12(2–3):195–201

    CAS  Google Scholar 

  • Ludewig K, Geyer MA, Vollenweider FX (2002) Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia. Schizophr Res 55(1–2):129–137

    Article  PubMed  Google Scholar 

  • Ludewig K, Geyer MA, Vollenweider FX (2003) Deficits in prepulse inhibition and habituation in never-medicated first-episode schizophrenia. Biol Psychiatry 54:121–128

    Article  PubMed  Google Scholar 

  • Mazoyer B, Zago L, Mellet E, Bricogne S, Etard O, Houde O, Crivello F, Joliot M, Petit L, Tzourio-Mazoyer N (2001) Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res Bull 54:287–298

    Article  PubMed  CAS  Google Scholar 

  • McNamara D, Larson DM, Rapoport SI, Soncrant TT (1990) Preferential metabolic activation of subcortical brain areas by acute administration of nicotine to rats. J Cereb Blood Flow Metab 10:48–56

    PubMed  CAS  Google Scholar 

  • Nagata K, Shinohara T, Kanno I, Hatzawa J, Domino E (1995) Effects of tobacco cigarette smoking on cerebral blood flow in normal adults. In: Domino EF (ed) Brain imaging of nicotine and tobacco smoking. NPP, Ann Arbor, pp 95–107

    Google Scholar 

  • Nyback H, Nordberg A, Langstrom B, Halldin C, Hartvig P, Ahlin A, Swahn CG, Sedvall G (1989) Attempts to visualize nicotinic receptors in the brain of monkey and man by positron emission tomography. Prog Brain Res 79:313–319

    Article  PubMed  CAS  Google Scholar 

  • Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent blood oxygenation. Proc Natl Acad Sci U S A 8868–8872

  • Russell MAH, Jarvis MJ, Jones G, Feyerabend C (1990) Non-smokers show acute tolerance to subcutaneous nicotine. Pscyhopharmacology 102:56–58

    Article  PubMed  CAS  Google Scholar 

  • Sacco KA, Bannon KL, George TP (2004) Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. J Psychopharmacol 18(4):457–474

    Article  PubMed  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(6):649–659

    Article  PubMed  Google Scholar 

  • Schwarzkopf SB, McCoy L, Smith DA, Boutros NN (1993) Test–retest reliability of prepulse inhibition of the acoustic startle response. Biol Psychiatry 33:815–828

    Article  PubMed  CAS  Google Scholar 

  • Semenova S, Bespalov A, Markou A (2003) Decreased prepulse inhibition during nicotine withdrawal in DBA/2J mice is reversed by nicotine self-administration. Eur J Pharmacol 472(1–2):99–110

    Article  PubMed  CAS  Google Scholar 

  • Simpson JR Jr, Snyder AZ, Gusnard DA, Raichle ME (2001) Emotion-induced changes in human medial prefrontal cortex: I. During cognitive task performance. Proc Natl Acad Sci U S A 98:683–687

    Article  PubMed  CAS  Google Scholar 

  • Spielewoy C, Markou A (2004) Strain-specificity in nicotine attenuation of phencyclidine-induced disruption of prepulse inhibition in mice: relevance to smoking in schizophrenia patients. Behav Genet 34(3):343–354

    Article  PubMed  Google Scholar 

  • Stein EA, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG, Hawkins M, Rao SM, Bandettini PA, Bloom AS (1998) Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 155:1009–10015

    PubMed  CAS  Google Scholar 

  • Stevens KE, Wear KD (1997) Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 57(4):869–874

    Article  PubMed  CAS  Google Scholar 

  • Stevens KE, Kem WR, Mahnir VM, Freedman R (1998) Selective alpha-7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology 136:320–327

    Article  PubMed  CAS  Google Scholar 

  • Stitt CL, Hoffman HS, Marsh RR, Schwartz GM (1976) Modification of the pigeon’s visual startle reaction by the sensory environment. J Comp Physiol Psychol 90:601–619

    Article  PubMed  CAS  Google Scholar 

  • Suemaru K, Yasuda K, Umeda K, Araki H, Shibata K, Choshi T, Hibino S, Gomita Y (2004) Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors. Br J Pharmacol 142(5):843–850

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Geyer MA (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 24:285–301

    PubMed  CAS  Google Scholar 

  • Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology 156(2–3):194–215

    Article  PubMed  CAS  Google Scholar 

  • Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme, Stuttgart

    Google Scholar 

  • Uck A, Polat A, Bozkurt O, Meteris H (2004) Cigarette smoking among patients with schizophrenia and bipolar disorders. Psychiatry Clin Neurosci 58(4):434–437

    Article  PubMed  Google Scholar 

  • Warburton DM (1990) Nicotine as a cognitive enhancer. In: Yamashita I (ed) Clinical neuropharmacology. Raven, New York, pp 579–580

    Google Scholar 

Download references

Acknowledgements

VK was supported by the Wellcome Trust, UK (067427/427/Z/02/Z). MAG was supported in part by the National Institute of Mental Health, US (MH42228) and the US Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. MAG has an equity interest in Sand Diego Instruments, Inc.

Author information

Authors and Affiliations

  1. Department of Psychology, P078, Institute of Psychiatry, King’s College London, De Crespigny Park, London, SE5 8AF, UK

    Peggy Postma, Jeffrey A. Gray & Veena Kumari

  2. Department of Psychology, City University, London, UK

    Peggy Postma & Melissa Hines

  3. Clinical Neuroscience Research Centre, Kent, UK

    Tonmoy Sharma

  4. Department of Psychiatry, University of California, San Diego, CA, USA

    Mark Geyer

  5. Division of Psychological Medicine, Institute of Psychiatry, King’s College London, London, UK

    Ravi Mehrotra, Mrigen Das & Elizabeth Zachariah

  6. Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London, UK

    Steven C. R. Williams

Authors
  1. Peggy Postma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey A. Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tonmoy Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark Geyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ravi Mehrotra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mrigen Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elizabeth Zachariah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melissa Hines
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Steven C. R. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Veena Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Veena Kumari.

Additional information

Jeffrey A. Gray is deceased.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Postma, P., Gray, J.A., Sharma, T. et al. A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia. Psychopharmacology 184, 589–599 (2006). https://doi.org/10.1007/s00213-006-0307-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0307-5

Keywords

Search

Navigation