Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization
- First Online:
- 2.3k Downloads
Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction.
Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function.
Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function.
Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder.
Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.
KeywordsNicotine Attention Learning Memory Hippocampus Amygdala Alzheimer's disease Schizophrenia ADHD
- Bartus RT, Dean RL, Flicker C (1987) Cholinergic psychopharmacology: an integration of human and animal research on memory. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven, New York, pp 219–232Google Scholar
- Bernert G, Sustrova M, Sovcikova E, Seidl R, Lubec G (2001) Effects of a single transdermal nicotine dose on cognitive performance in adults with Down syndrome. J Neural Transm, Suppl 61:237–245Google Scholar
- Biederman J (1998) Attention-deficit/hyperactivity disorder: a life-span perspective. J Clin Psychiatry 7:4–16Google Scholar
- Brody AL, Olmstead RE, London ED, Farahi J, Meyer JH, Grossman P, Lee GS, Huang J, Hahn EL, Mandelkern MA (2004) Smoking-induced ventral striatum dopamine release. Am J Epidemiol 161:1211–1218Google Scholar
- Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev, Neurosci 3:617–628Google Scholar
- Changeux JP (1990a) Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligand-gated ion channel. FIDA Research Foundation Neuroscience Award Lectures. Raven, New York, pp 21–168Google Scholar
- Court JA, Piggott MA, Lloyd S, Cookson N, Ballard CG, McKeith IG, Perry RH, Perry EK (2000b) Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication. Neuroscience 98:79–87CrossRefPubMedGoogle Scholar
- Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier LGD, Bencherif M (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev 10:147–166PubMedCrossRefGoogle Scholar
- Grigoryan GA, Mitchell SN, Hodges H, Sinden JD, Gray JA (1994) Are the cognitive-enhancing effects of nicotine in the rat with lesions to the forebrain cholinergic projection system mediated by an interaction with the noradrenergic system? Pharmacol Biochem Behav 49:511–521CrossRefPubMedGoogle Scholar
- Heishman SJ, Taylor RC, Henningfield JE (1994) Nicotine and smoking: a review of effects on human performance. Exp Clin Psychopharmacol 2:1–51Google Scholar
- Jackson WJ, Elrod K, Buccafusco JJ (1989) Delayed matching-to-sample in monkeys as a model for learning and memory deficits: role of brain nicotinic receptors. In: Meyer EM, Simpkins JW, Yamamoto J (eds) Novel approaches to the treatment of Alzheimer's disease. Plenum, New York, pp 39–52Google Scholar
- Kollins SH, McClernon FJ, Fuemmeler BF (2005) Association between smoking and ADHD symptoms in a population-based sample of young adults. Arch Gen Psychiatry (in press)Google Scholar
- Levin ED (1999) Persisting effects of chronic adolescent nicotine administration on radial-arm maze learning and response to nicotinic challenges. Neurobehavioral Teratology Society Annual Meeting, Keystone, COGoogle Scholar
- Levin ED (2000a) The role of nicotinic acetylcholine receptors in cognitive function. In: Clementi F, Gotti C, Fornasari D (eds) Handbook of experimental pharmacology: neuronal nicotinic receptors. Springer, Berlin Heidelberg New York, pp 587–602Google Scholar
- Levin ED (2000b) Use of the radial-arm maze to assess learning and memory. In: Buccafusco JJ (ed) Methods in behavioral pharmacology. CRC, New York, pp 189–199Google Scholar
- Levin ED (2001) Nicotine effects on attention deficit hyperactivity disorder. In: Levin ED (ed) Nicotinic receptors in the nervous system. CRC, New York, pp 251–260Google Scholar
- Levin ED, Rose JE (1992) Cognitive effects of D1 and D2 interactions with nicotinic and muscarinic systems. In: Levin ED, Decker MW, Butcher LL (eds) Neurotransmitter interactions and cognitive function. Berkhäuser, Boston, pp 144–158Google Scholar
- Levin ED, Kim P, Meray R (1996c) Chronic nicotine effects on working and reference memory in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs. Psychopharmacology (Berl) 127:25–30Google Scholar
- Levin ED, Toll K, Chang G, Christopher NC, Briggs SJ (1996d) Epibatidine, a potent nicotinic agonist: effects on learning and memory in the radial-arm maze. Med Chem Res 6:543–554Google Scholar
- Levin ED, Simon BB, Conners CK (2000) Nicotine effects and attention deficit disorder. In: Newhouse P, Piasecki M (eds) Nicotine in psychiatry: psychopathology and emerging therapeutics. Wiley, New York, pp 203–214Google Scholar
- Levin ED, Sledge D, Baruah A, Addy N (2003) Hippocampal NMDA blockade and nicotinic effects on memory function. Behav Brain Res 61:489–495Google Scholar
- Levin ED, Blackwelder WP, Lau E, Brotherton J (2004a) Nicotinic alpha4-beta2 and alpha7 nicotinic antagonist effects in the mediodorsal thalamic nucleus and frontal cortex on memory function. Society for Neuroscience, Annual Meeting, San Diego, CAGoogle Scholar
- Levin ED, Icenogle L, Farzad A (2005a) Nicotine-induced working memory improvement attenuated by the 5-HT2A antagonist ketanserin. Society for Research on Nicotine and Tobacco, Prague, Czech RepublicGoogle Scholar
- Levin ED, Limpuangthip J, Rachakonda T (2005b) Timing of nicotine effects on learning in zebrafish. Psychopharmacology (Berl) (in press)Google Scholar
- Myers CS, Robles O, Kakoyannis AN, Sherr JD, Avila MT, Blaxton TA, Thaker GK (2004) Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology (Berl) 174:334–340Google Scholar
- Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL (1988) Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl) 95:171–175Google Scholar
- Passetti F, Dalley JW, Robbins TW (2003) Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task. Psychopharmacology (Berl) 165:136–145Google Scholar
- Rupniak NMJ, Iversen SD (1989) Comparison of cognitive facilitation by cholinomimetic drugs in two primate memory tests. J Psychopharmacol 3:52PGoogle Scholar
- Terry AV, Risbrough VB, Buccafusco JJ, Menzaghi F (2002) Effects of (+/−)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a selective ligand for nicotinic acetylcholine receptors, in tests of visual attention and distractibility in rats and monkeys. J Pharmacol Exp Ther 301:284–292CrossRefPubMedGoogle Scholar
- Utsuki T, Shoaib M, Holloway HW, Ingram DK, Wallace WC, Haroutunian V, Sambamurti K, Lahiri DK, Greig NH (2002) Nicotine lowers the secretion of the Alzheimer's amyloid beta-protein precursor that contains amyloid beta-peptide in rat. J Alzheimer's Dis 4:405–415Google Scholar
- Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, Soriano J, Fine C, Abrams A, Rater M, Polisner D (1999) A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry 156:1931–1937PubMedGoogle Scholar
- Wonnacott S, Irons J, Rapier C, Thorne B, Lunt GG (1989) Presynaptic modulation of transmitter release by nicotinic receptors. In: Nordberg A, Fuxe K, Holmstedt B, Sundwall A (eds) Progress in brain research. Elsevier Science Publishers B.V., pp 157–163Google Scholar