Abstract
Rationale
Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known.
Objectives
In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2 subunit-containing nAChR gene (β2+/− or β2−/−) performing an operant cognitive flexibility task.
Results
Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2−/− mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/− mice.
Conclusions
Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies.
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References
Amitai N, Markou A (2009) Chronic nicotine improves cognitive performance in a test of attention but does not attenuate cognitive disruption induced by repeated phencyclidine administration. Psychopharmacology 202:275–286
Bailey CD, De Biasi M, Fletcher PJ, Lambe EK (2010) The nicotinic acetylcholine receptor alpha5 subunit plays a key role in attention circuitry and accuracy. J Neurosci 30:9241–9252
Benowitz NL (1996) Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 18:188–204
Besson M, Granon S, Mameli-Engvall M, Cloez-Tayarani I, Maubourguet N, Cormier A, Cazala P, David V, Changeux JP, Faure P (2007) Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci U S A 104:8155–8160
Beveridge TJ, Gill KE, Hanlon CA, Porrino LJ (2008) Review. Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys. Philos Trans R Soc Lond Ser B Biol Sci 363:3257–3266
Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM, Colbran RJ, Alvarez VA, Nakazawa K, Delpire E, Lovinger DM, Holmes A (2010) Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30:4590–4600
Chan WK, Wong PT, Sheu FS (2007) Frontal cortical alpha7 and alpha4beta2 nicotinic acetylcholine receptors in working and reference memory. Neuropharmacology 52:1641–1649
Changeux JP (2010) Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11:389–401
Clarke HF, Robbins TW, Roberts AC (2008) Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex. J Neurosci 28:10972–10982
Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD 3rd, O’Neill BT (2005) Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48:3474–3477
Cosgrove KP, Batis J, Bois F, Maciejewski PK, Esterlis I, Kloczynski T, Stiklus S, Krishnan-Sarin S, O’Malley S, Perry E, Tamagnan G, Seibyl JP, Staley JK (2009) beta2-Nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking. Arch Gen Psychiatry 66:666–676
Crunelle CL, Miller ML, Booij J, van den Brink W (2010) The nicotinic acetylcholine receptor partial agonist varenicline and the treatment of drug dependence: a review. Eur Neuropsychopharmacol 20:69–79
Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694
D’Amore DE, Tracy BA, Parikh V (2013) Exogenous BDNF facilitates strategy set-shifting by modulating glutamate dynamics in the dorsal striatum. Neuropharmacology 75:312–323
Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729
Dani JA, De Biasi M (2001) Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70:439–446
Darvas M, Palmiter RD (2011) Contributions of striatal dopamine signaling to the modulation of cognitive flexibility. Biol Psychiatry 69:704–707
De Biasi M, Dani JA (2011) Reward, addiction, withdrawal to nicotine. Annu Rev Neurosci 34:105–130
Demeter E, Sarter M (2013) Leveraging the cortical cholinergic system to enhance attention. Neuropharmacology 64:294–304
Dunnett SB, Martel FL (1990) Proactive interference effects on short-term memory in rats: I. Basic parameters and drug effects. Behav Neurosci 104:655–665
Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489
Featherstone RE, Rizos Z, Kapur S, Fletcher PJ (2008) A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or long-term memory. Behav Brain Res 189:170–179
Feduccia AA, Chatterjee S, Bartlett SE (2012) Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions. Front Mol Neurosci 5:83
Floresco SB, Ghods-Sharifi S, Vexelman C, Magyar O (2006) Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J Neurosci 26:2449–2457
Floresco SB, Block AE, Tse MT (2008) Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure. Behav Brain Res 190:85–96
Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 27:482–491
Gotti C, Moretti M, Gaimarri A, Zanardi A, Clementi F, Zoli M (2007) Heterogeneity and complexity of native brain nicotinic receptors. Biochem Pharmacol 74:1102–1111
Gould TJ (2010) Addiction and cognition. Addict Sci Clin Pract 5:4–14
Govind AP, Vezina P, Green WN (2009) Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 78:756–765
Grady SR, Wageman CR, Patzlaff NE, Marks MJ (2012) Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include alpha5 or alpha6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology 62:1935–1943
Guillem K, Bloem B, Poorthuis RB, Loos M, Smit AB, Maskos U, Spijker S, Mansvelder HD (2011) Nicotinic acetylcholine receptor beta2 subunits in the medial prefrontal cortex control attention. Science 333:888–891
Haluk DM, Floresco SB (2009) Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology 34:2041–2052
Hatsukami DK, Ebbert JO, Anderson A, Lin H, Le C, Hecht SS (2007) Smokeless tobacco brand switching: a means to reduce toxicant exposure? Drug Alcohol Depend 87:217–224
Hilario MR, Turner JR, Blendy JA (2012) Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. Neuropsychopharmacology 37:2661–2670
Howe WM, Ji J, Parikh V, Williams S, Mocaer E, Trocme-Thibierge C, Sarter M (2010) Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35:1391–1401
Hughes JR, Peters EN, Naud S (2008) Relapse to smoking after 1 year of abstinence: a meta-analysis. Addict Behav 33:1516–1520
Izquierdo A, Jentsch JD (2012) Reversal learning as a measure of impulsive and compulsive behavior in addictions. Psychopharmacology 219:607–620
Jarvis MJ, Russell MA, Benowitz NL, Feyerabend C (1988) Elimination of cotinine from body fluids: implications for noninvasive measurement of tobacco smoke exposure. Am J Public Health 78:696–698
Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatr 162:1403–1413
Kehagia AA, Murray GK, Robbins TW (2010) Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol 20:199–204
Kenny PJ, Markou A (2006) Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31:1203–1211
Kolokotroni KZ, Rodgers RJ, Harrison AA (2012) Effects of chronic nicotine, nicotine withdrawal and subsequent nicotine challenges on behavioural inhibition in rats. Psychopharmacology 219:453–468
Laughlin RE, Grant TL, Williams RW, Jentsch JD (2011) Genetic dissection of behavioral flexibility: reversal learning in mice. Biol Psychiatry 69:1109–1116
Laviolette SR, van der Kooy D (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5:55–65
Leslie FM, Mojica CY, Reynaga DD (2013) Nicotinic receptors in addiction pathways. Mol Pharmacol 83:753–758
Levin ED, Christopher NC, Briggs SJ (1997) Chronic nicotine agonist and antagonist effects on T-maze alternation. Physiol Behav 61:863–866
Levin ED, Bradley A, Addy N, Sigurani N (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757–765
Liu L, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR (2012) Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing alpha4 and alpha6 subunits. Mol Pharmacol 81:541–548
Lovejoy E (1968) Attention in discrimination learning; a point of view and a theory. Holden-Day, San Francisco
Marks MJ, Stitzel JA, Collins AC (1985) Time course study of the effects of chronic nicotine infusion on drug response and brain receptors. J Pharmacol Exp Ther 235:619–628
McCallum SE, Parameswaran N, Bordia T, Fan H, Tyndale RF, Langston JW, McIntosh JM, Quik M (2006) Increases in alpha4* but not alpha3*/alpha6* nicotinic receptor sites and function in the primate striatum following chronic oral nicotine treatment. J Neurochem 96:1028–1041
McCracken CB, Grace AA (2013) Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. J Neurosci 33:17469–17482
McGaughy J, Decker MW, Sarter M (1999) Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats. Psychopharmacology 144:175–182
Muir JL (1996) Attention and stimulus processing in the rat. Brain Res Cogn Brain Res 3:215–225
Nesic J, Rusted J, Duka T, Jackson A (2011) Degree of dependence influences the effect of smoking on cognitive flexibility. Pharmacol Biochem Behav 98:376–384
Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36–46
Ortega LA, Tracy BA, Gould TJ, Parikh V (2013) Effects of chronic low- and high-dose nicotine on cognitive flexibility in C57BL/6J mice. Behav Brain Res 238:134–145
Pattij T, Janssen MC, Loos M, Smit AB, Schoffelmeer AN, van Gaalen MM (2007) Strain specificity and cholinergic modulation of visuospatial attention in three inbred mouse strains. Genes Brain Behav 6:579–587
Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552
Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177
Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84:329–342
Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Changeux JP, Maskos U, Fratta W (2008) Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J Neurosci 28:12318–12327
Portugal GS, Kenney JW, Gould TJ (2008) Beta2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning. Neurobiol Learn Mem 89:106–113
Ragozzino ME (2007) The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 1121:355–375
Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond Ser B Biol Sci 363:3137–3146
Sacco KA (2001) Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment. Eur J Pharmacol 417:117–123
Sarter M, Paolone G (2011) Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches. Behav Neurosci 125:825–835
Scheggia D, Bebensee A, Weinberger DR, Papaleo F (2014) The ultimate intra-/extra-dimensional attentional set-shifting task for mice. Biol Psychiatry 75:660–670
Schoenbaum G, Saddoris MP, Stalnaker TA (2007) Reconciling the roles of orbitofrontal cortex in reversal learning and the encoding of outcome expectancies. Ann N Y Acad Sci 1121:320–335
Semenova S, Stolerman IP, Markou A (2007) Chronic nicotine administration improves attention while nicotine withdrawal induces performance deficits in the 5-choice serial reaction time task in rats. Pharmacol Biochem Behav 87:360–368
Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, Perry E, Dubin JA, Estok K, Brenner E, Baldwin RM, Tamagnan GD, Seibyl JP, Jatlow P, Picciotto MR, London ED, O’Malley S, van Dyck CH (2006) Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci 26:8707–8714
Stalnaker TA, Takahashi Y, Roesch MR, Schoenbaum G (2009) Neural substrates of cognitive inflexibility after chronic cocaine exposure. Neuropharmacology 56(Suppl 1):63–72
Stolerman IP, Mirza NR, Hahn B, Shoaib M (2000) Nicotine in an animal model of attention. Eur J Pharmacol 393:147–154
Turner JR, Castellano LM, Blendy JA (2010) Nicotinic partial agonists varenicline and sazetidine-A have differential effects on affective behavior. J Pharmacol Exp Ther 334:665–672
Turner JR, Wilkinson DS, Poole RL, Gould TJ, Carlson GC, Blendy JA (2013) Divergent functional effects of sazetidine-A and varenicline during nicotine withdrawal. Neuropsychopharmacology 38:2035–2047
Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F (2011) Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci U S A 108:15037–15042
Walters CL, Brown S, Changeux JP, Martin B, Damaj MI (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacology 184:339–344
Wilkinson DS, Turner JR, Blendy JA, Gould TJ (2013) Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology 225:201–208
Xu W, Orr-Urtreger A, Nigro F, Gelber S, Sutcliffe CB, Armstrong D, Patrick JW, Role LW, Beaudet AL, De Biasi M (1999) Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4 subunits of neuronal nicotinic acetylcholine receptors. J Neurosci 19:9298–9305
Young JW, Finlayson K, Spratt C, Marston HM, Crawford N, Kelly JS, Sharkey J (2004) Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor. Neuropsychopharmacology 29:891–900
Young JW, Crawford N, Kelly JS, Kerr LE, Marston HM, Spratt C, Finlayson K, Sharkey J (2007) Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice. Eur Neuropsychopharmacol 17:145–155
Young JW, Meves JM, Geyer MA (2013) Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test. Behav Brain Res 240:119–133
Acknowledgments
The studies were supported by Brain and Behavior Research Foundation (V.P.) and partly by grants from the National Institute of Health (NIH) DA 017949 and CA 143187 (T.J.G.). D.G. was supported by MARC Undergraduate Student Training in Academic Research (NIH 5T34 GM 087239). We thank David Braak for the assistance with the genotyping.
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Cole, R.D., Poole, R.L., Guzman, D.M. et al. Contributions of β2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice. Psychopharmacology 232, 1207–1217 (2015). https://doi.org/10.1007/s00213-014-3754-4
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DOI: https://doi.org/10.1007/s00213-014-3754-4