Abstract
Background and rationale
Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).
Methods
Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.
Results
Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01–1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment.
Conclusions
AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.
Similar content being viewed by others
References
Buccafusco JJ, Terry AV Jr (2009) A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists. Biochem Pharmacol 78:852–862
Bushnell P (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259
Changeux JP, Bertrand D, Corringer PJ, Dehaene S, Edelstein S, Lena C, LeNovere N, Marubio L, Picciotto M, Zoli M (1998) Brain nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Res Rev 26:198–216
Cincotta SL, Yorek MS, Moschak TM, Lewis SR, Rodefer JS (2008) Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction. Curr Opin Investig Drugs 9:47–56
Dunbar GC, Inglis F, Kuchibhatla R, Sharma T, Tomlinson M, Wamsley J (2007) Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI). J Psychopharmacol 21:171–181
Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier L, Dunbar G, Bencherif M (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Rev 10:147–166
Grilly DM (2000) A verification of psychostimulant-induced improvement in sustained attention in rats: effects of d-amphetamine, nicotine, and pemoline. Exp Clin Psychopharmacol 8:14–21
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
Hahn B, Shoaib M, Stolerman IP (2011) Selective nicotinic receptors antagonists: effects on attention and nicotine-induced attentional enhancement. Psychopharmacology 217:75–82
Hahn B, Stolerman IP (2002) Nicotine-induced attentional enhancement in rats: effects of chronic exposure to nicotine. Neuropsychopharmacology 27:712–722
Howe WM, Ji J, Parikh V, Williams S, Mocaër E, Trocmé-Thibierge C, Sarter M (2010) Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35:1391–1401
Janowsky DS, Overstreet DH, Nurnberger JI Jr (1994) Is cholinergic sensitivity a genetic marker for the affective disorders? Am J Med Genet 54:335–344
Kim H, Flanagin BA, Qin C, MacDonald RL, Stitzel JA (2003) The mouse Chrna4 A529T polymorphism alters the ratio of high to low affinity alpha4 beta2 nAchRs. Neuropharmacology 45:345–354
Lawrence NS, Ross TJ, Stein EA (2002) Cognitive mechanisms of nicotine on visual attention. Neuron 36:539–548
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, Rose JE (1998) Transdermal nicotine effects on attention. Psychopharmacology 140:135–141
Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996) Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology 123:55–63
Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification and anatomic localization. Psychopharmacology 184:523–539
Lippiello PM, Benchierif M, Gray JA, Peters S, Grigoryan G, Hodges H, Collins AC (1996) RJR-2403: a nicotinic agonist with CNS selectivity II. In vivo characterization J Pharmacol Exp Therap 279:1422–1429
Locke SM, Newhouse PA, Mazzulla E, Wilkins H, Potter AS (2010) Novel nicotinic agonist AZD3480 improves cognition in a randomized control trial of adults with attention-deficit/hyperactivity disorder. Presented at the Society for Neuroscience Annual Meeting, San Diego CA, 13–17 November 2010; Abstract# 563.17
McEvoy JP, Allen TB (2002) The importance of nicotinic acetylcholine in schizophrenia, bipolar disorder and Tourette's syndrome. Curr Drug Targets CNC Neuronal Disord 1:433–442
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
Mirza NR, Bright JL (2001) Nicotine-induced enhancements in the five-choice serial reaction time task in rats are strain-dependent. Psychopharmacology 154:8–12
Mirza NR, Stolerman IP (1998) Nicotine enhances sustained attention in the rat under specific task conditions. Psychopharmacology 138:266–274
Mirza NR, Stolerman IP (2000) The role of nicotinic and muscarinic acetylcholine receptors in attention. Psychopharmacology 148:243–250
Muir JL, Everitt BJ, Robbins TW (1995) Reversal of visual attentional dysfunction following lesions of the cholinergic basal forebrain by physostigmine and nicotine but not by the 5-HT3 receptor antagonist, ondansetron. Psychopharmacology 118:82–92
Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Cur Opin Pharmacol 4:36–46
Papke R, Webster J, Lippiello P, Bencherif M, Francis M (2000) The activation and inhibition of human nicotinic acetylcholine receptor by RJR-2403 indicate a selectivity for the alpha4beta2 receptor subtype. J Neurochem 75:204–216
Rezvani AH, Caldwell DP, Levin ED (2004) Nicotine-antipsychotic drug interactions and attentional performance. Eur J Pharmacol 486:175–182
Rezvani AH, Cauley M, Sexton H, Xiao Y, Brown M, Paige M, McDowell B, Kellar K, Levin ED (2011) Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague Dawley rats. Psychopharmacology 215:621–630
Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED (2009a) Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:269–275
Rezvani AH, Kholdebarin E, Cauley MC, Dawson E, Levin ED (2009b) Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats. Pharmacol Biochem Behav 92:141–146
Rezvani AH, Kholdebarin E, Dawson E, Levin ED (2008) Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats. Int J Neuropsychopharmacol 11:63–70
Rezvani AH, Levin ED (2003) Nicotine interactions with the NMDA glutaminergic antagonist dizocilpine and attentional function. Eur J Pharmacol 465:83–90
Rezvani AH, Levin ED (2004) Nicotine-antipsychotic drug interactions and attentional performance in female rats. Eur J Pharmacol 486:175–182
Sarter M, Parikh V, Howe WM (2009) nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms. Biochem Pharmacol 78:658–667
Stolerman IP, Mirza NR, Hahn B, Shoaib M (2000) Nicotine in an animal model of attention. Eur J Pharmacol 393:147–154
Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y (2002) Research and development of donepezil hydrochloride, a new type of acetylcholinestrase inhibitor. Jpn J Pharmacol 89:7–20
Terry AVJ, 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 301:284–292
Von Euler G, Bertrand D, Johnson EC (2011) Comparison of pharmacological properties of AZD3480 and AZD1446 on neuronal nicotinic receptor subtypes. Soc Neurosci (Abstract #336.11)
White HK, Levin ED (1999) Chronic four week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 143:158–165
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 Psychiat 156:1931–1937
Young J, Finlayson K, Spratt C, Marston H, Crawford N, Kelly J, Sharkey J (2004) Nicotine improves sustained attention in mice: evidence for involvement of the alpha 7 nicotinic acetylcholine receptor. Neuropsychopharmacology 29:891–900
Acknowledgements
This research was funded by AstraZeneca Pharmaceuticals in collaboration with Targacept, Inc. Dr. Edwin Johnson is an employee of AstraZeneca Pharmaceuticals. Dr. Gregory J. Gatto is an employee of Targacept, Inc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rezvani, A.H., Cauley, M.C., Johnson, E.C. et al. Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats. Psychopharmacology 223, 251–258 (2012). https://doi.org/10.1007/s00213-012-2712-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-012-2712-2