Abstract
The discovery of the role of nicotinic receptors in attention and memory has led to the testing of nicotinic analogs as cognitive enhancing agents in patient populations. Empirical information about nicotine's ability to enhance elements of attention and memory in normal individuals might guide development of therapeutic uses of nicotine in cognitively impaired populations. The purpose of this study was to determine the effect of nicotine on continuous attention, working memory, and computational processing in tobacco-deprived and nondeprived smokers. A total of 28 smokers (14 men, 14 women) participated in a double-blind, placebo-controlled, within-subject study, in which they were overnight (12 h) tobacco deprived at one session and smoked ad libitum before the other session. At each session, participants received 0, 1, and 2 mg nicotine via nasal spray in random order at 90 min intervals. Before and after each dose, a battery of cognitive, subjective, and physiological measures was administered, and blood samples were taken for plasma nicotine concentration. Overnight tobacco deprivation resulted in impaired functioning on all cognitive tests and increased self-reports of tobacco craving and negative mood; nicotine normalized these deficits. In the nondeprived condition, nicotine enhanced performance on the continuous performance test (CPT) and an arithmetic test in a dose-related manner, but had no effect on working memory. In general, women were more sensitive than men to the subjective effects of nicotine. These results provide an unequivocal determination that nicotine enhanced attentional and computational abilities in nondeprived smokers and suggest these cognitive domains as substrates for novel therapeutic indications.
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References
American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association: Washington, DC.
Bancroft A, Levin ED (2000). Ventral hippocampal α4β2 nicotinic receptors and chronic nicotine effects on memory. Neuropharmacology 39: 2770–2778.
Bekker EM, Böcker KBE, Van Hunsel F, van den Berg MC, Kenemans JL (2005). Acute effects of nicotine on attention and response inhibition. Pharmacol Biochem Behav 82: 539–548.
Benowitz NL, Hatsukami DK (1998). Gender differences in the pharmacology of nicotine addiction. Addict Biol 3: 383–404.
Benowitz NL, Jacob P (1994). Meabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56: 483–493.
Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P (2006). Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 79: 480–488.
Bizarro L, Patel S, Murtagh C, Stolerman IP (2004). Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate. Behav Pharmacol 15: 195–206.
Buccafusco JJ, Jackson WJ (1991). Beneficial effects of nicotine administered prior to a delayed matching-to-sample task in young and aged monkeys. Neurobiol Aging 12: 233–238.
Chait LD, Corwin RL, Johanson CE (1988). A cumulative dosing procedure for administering marijuana smoke to humans. Pharmacol Biochem Behav 29: 553–557.
Cohen JD, Forman SD, Braver TS, Casey BJ, Servan-Schreiber D, Noll DC (1994). Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI. Hum Brain Mapp 1: 293–304.
Conners CK, Levin ED, Sparrow E, Hinton SC, Erhardt D, Meck WH et al (1996). Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD). Psychopharmacol Bull 32: 67–73.
Coull JT, Frith CD, Frackowiak RSJ, Grasby PM (1996). A fronto-parietal network for rapid visual information processing: a PET study of sustained attention and working memory. Neuropsychologia 34: 1085–1095.
Eissenberg T, Adams C, Riggins EC, Likness M (1999). Smokers' sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1: 317–324.
Ernst M, Matochik JA, Heishman SJ, Van Horn JD, Jons PH, Henningfield JE et al (2001). Effect of nicotine on brain activation during performance of a working memory task. Proc Natl Acad Sci 98: 4728–4733.
Felix R, Levin ED (1997). Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats. Neuroscience 81: 1009–1017.
File SE, Fluck E, Leahy A (2001). Nicotine has calming effects on stress-induced mood changes in females, but enhances aggressive mood in males. Int J Neuropsychopharmacol 4: 371–376.
Foulds J, Stapleton J, Swettenham J, Bell N, McSorley K, Russell MAH (1996). Cognitive performance effects of subcutaneous nicotine in smokers and never-smokers. Psychopharmacology 127: 31–38.
Fujita M, Ichise M, van Dyck CH, Zoghbi SS, Tamagnan G, Mukhin AG et al (2003). Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET. Eur J Nucl Med Mol Imaging 30: 1620–1629.
Gallezot JD, Bottlaender M, Gregoire MC, Roumenov D, Deverre JR, Coulon C et al (2005). In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med 46: 240–247.
Grobe JE, Perkins KA, Goettler-Good J, Wilson A (1998). Importance of environmental distractors in the effects of nicotine on short-term memory. Exp Clin Psychopharmacol 6: 209–216.
Grottick AJ, Higgins GA (2000). Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117: 197–208.
Guthrie SK, Zubieta J-K, Ohl L, Ni L, Koeppe RA, Minoshima S et al (1999). Arterial/venous plasma nicotine concentrations following nicotine nasal spray. Eur J Clin Pharmacol 55: 639–643.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO (1991). The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 86: 1119–1127.
Heishman SJ (1998). What aspects of human performance are truly enhanced by nicotine? Addiction 93: 317–320.
Heishman SJ, Henningfield JE (2000). Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers. Psychopharmacology 152: 321–333.
Heishman SJ, Singleton EG, Crouch DJ (1996). Laboratory validation study of Drug Evaluation and Classification program: ethanol, cocaine, and marijuana. J Anal Toxicol 20: 468–483.
Heishman SJ, Singleton EG, Moolchan ET (2003). Tobacco craving questionnaire: reliability and validity of a new multi-factorial instrument. Nicotine Tob Res 5: 645–654.
Heishman SJ, Snyder FR, Henningfield JE (1993). Performance, subjective, and physiological effects of nicotine in nonsmokers. Drug Alcohol Depend 34: 11–18.
Heishman SJ, Taylor RC, Henningfield JE (1994). Nicotine and smoking: a review of effects on human performance. Exp Clin Psychopharmacol 2: 345–395.
Henningfield JE (1995). Nicotine medications for smoking cessation. N Engl J Med 333: 1196–1203.
Hughes JR (1991). Distinguishing withdrawal relief and direct effect of smoking. Psychopharmacology 104: 409–410.
James JE, Rogers PJ (2005). Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation. Psychopharmacology 182: 1–8.
Johansson C-J, Olsson P, Bende M, Carlsson T, Gunnarsson PO (1991). Absolute bioavailability of nicotine applied to different nasal regions. Eur J Clin Pharmacol 41: 585–588.
Kelton MC, Kahn HJ, Conrath CL, Newhouse PA (2000). The effects of nicotine on Parkinson's disease. Brain Cogn 43: 274–282.
Kleykamp BA, Jennings JM, Blank MD, Eissenberg TE (2005). The effects of nicotine on attention and working memory in never-smokers. Psychol Addict Beh 19: 433–438.
Koelega HS (1993). Stimulant drugs and vigilance: a review. Psychopharmacology 111: 1–16.
Kumari V, Gray JA, ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E et al (2003). Cognitive effects of nicotine in humans: an fMRI study. NeuroImage 19: 1002–1013.
Landers DM, Crews DJ, Boutcher SH, Skinner JS, Gustafsen S (1992). The effects of smokeless tobacco on performance and psychophysiological response. Med Sci Sports Exercise 24: 895–903.
Lawrence NS, Ross TJ, Stein EA (2002). Cognitive mechanisms of nicotine on visual attention. Neuron 36: 539–548.
Levin ED, Bettegowda C, Blosser J, Gordon J (1999). AR-R17779, an alpha7 nicotinic agonist, improves learning and memory in rats. Behav Pharmacol 10: 675–680.
Levin ED, Christopher NC (2002). Persistence of nicotinic agonist RJR 2403 induced working memory improvement in rats. Drug Dev Res 55: 97–103.
Levin ED, Conners CK, Silva D, Hinton SC, Meck WH, March J et al (1998). Transdermal nicotine effects on attention. Psychopharmacology 140: 135–141.
Levin ED, Kaplan S, Boardman A (1997). Acute nicotine interactions with nicotinic and muscarinic antagonists: working and reference memory effects in the 16-arm radial maze. Behav Pharmacol 8: 236–242.
Levin ED, McClernon FJ, Rezvani AH (2006). Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 184: 523–539.
Levin ED, Wilson W, Rose JE, McEvoy J (1996). Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15: 429–436.
McClernon FJ, Gilbert DG, Radtke R (2003). Effects of transdermal nicotine on lateralized identification and memory interference. Hum Psychopharmacol Clin Exp 18: 339–343.
Min SK, Moon IW, Ko RW, Shin HS (2001). Effects of transdermal nicotine on attention and memory in healthy elderly non-smokers. Psychopharmacology 159: 83–88.
Myers CS, Robles O, Kakoyannis AN, Sherr JD, Avila MT, Blaxton TA et al (2004). Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology 174: 334–340.
National Cancer Institute (2003). Those Who Continue to Smoke: Is Achieving Abstinence Harder and Do We Need to Change our Interventions?. US Department of Health and Human Services: Bethesda, MD.
Park S, Knopick C, McGurk S, Meltzer HY (2000). Nicotine impairs spatial working memory while leaving spatial attention intact. Neuropsychopharmacology 22: 200–209.
Perkins KA, DiMarco A, Grobe JE, Scierka A, Stiller RL (1994). Nicotine discrimination in male and female smokers. Psychopharmacology 116: 407–413.
Perkins KA, Donny E, Caggiula AR (1999). Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1: 301–315.
Perkins KA, Epstein LH, Stiller R, Jennings JR, Christiansen C, McCarthy T (1986). An aerosol spray alternative to cigarette smoking in the study of the behavioral and physiological effects of nicotine. Behav Res Methods Instrum Comput 18: 420–426.
Perkins KA, Sanders M, D'Amico D, Wilson A (1997). Nicotine discrimination and self-administration in humans as a function of smoking status. Psychopharmacology 131: 361–370.
Pritchard WS (1991). Electroencephalographic effects of cigarette smoking. Psychopharmacology 104: 485–490.
Rezvani AH, Caldwell DP, Levin ED (2004). Nicotine-antipsychotic drug interactions and attentional performance. Eur J Pharmacol 486: 175–182.
Schuh KJ, Schuh LM, Henningfield JE, Stitzer ML (1997). Nicotine nasal spray and vapor inhaler: abuse liability assessment. Psychopharmacology 130: 352–361.
Seidl R, Tiefenthaler M, Hauser E, Lubec G (2000). Effects of transdermal nicotine on cognitive performance in Down's syndrome. Lancet 356: 1409–1410.
Sherwood N (1993). Effects of nicotine on human psychomotor performance. Hum Psychopharmacol Exp Clin 8: 155–184.
Shipley WC (1946). Institute of Living Scale. Western Psychological Services: Los Angeles.
Snyder FR, Henningfield JE (1989). Effects of nicotine administration following 12 h of tobacco deprivation: assessment on computerized performance tasks. Psychopharmacology 97: 17–22.
Socci DJ, Sanberg PR, Arendash GW (1995). Nicotine enhances Morris water maze performance of young and aged rats. Neurobiol Aging 16: 857–860.
Sutherland G, Russell MAH, Stapleton J, Feyerabend C, Ferno O (1992). Nasal nicotine spray: a rapid nicotine delivery system. Psychopharmacology 108: 512–518.
Trimmel M, Wittberger S (2004). Effects of transdermally administered nicotine on aspects of attention, task load, and mood in women and men. Pharmacol Biochem Behav 78: 639–645.
Van Kampen M, Selbach K, Schneider R, Schiegel E, Boess F, Schreiber R (2004). AR-R17779 improves social recognition in rats by activation of nicotinic alpha7 receptors. Psychopharmacology 172: 375–383.
White HK, Levin ED (1999). Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 143: 158–165.
Wonnacott S (1997). Presynaptic nicotinic Ach receptors. Trends Neurosci 20: 92–98.
Acknowledgements
We thank Dr Kenneth Perkins for information on preparing the placebo nasal spray and John Etter for his excellent assistance in the conduct of the study.
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This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. The authors declare there are no conflicting financial interests to disclose.
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Myers, C., Taylor, R., Moolchan, E. et al. Dose-Related Enhancement of Mood and Cognition in Smokers Administered Nicotine Nasal Spray. Neuropsychopharmacol 33, 588–598 (2008). https://doi.org/10.1038/sj.npp.1301425
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DOI: https://doi.org/10.1038/sj.npp.1301425
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