Psychopharmacology

, Volume 226, Issue 1, pp 35–43 | Cite as

Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats

  • Amir H. Rezvani
  • Marty Cauley
  • Yingxian Xiao
  • Kenneth J. Kellar
  • Edward D. Levin
Original Investigation

Abstract

Rationale

Nicotine and nicotinic agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all nicotinic agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of nicotinic agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at α4β2 nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine.

Methods

In the current study, we tested the effects of chronic subcutaneous infusion of sazetidine-A (0, 2, or 6 mg/kg/day) on attention in Sprague-Dawley rats. Furthermore, we investigated the effects of chronic sazetidine-A treatment on attentional impairment induced by an acute administration of 0.02 mg/kg scopolamine.

Results

During the first week period, the 6-mg/kg/day sazetidine-A dose significantly reversed the attentional impairment induced by scopolamine. During weeks 3 and 4, the scopolamine-induced impairment was no longer seen, but sazetidine-A (6 mg/kg/day) significantly improved attentional performance on its own. Chronic sazetidine-A also reduced response latency and response omissions.

Conclusions

This study demonstrated that similar to its acute effects, chronic infusions of sazetidine-A improve attentional performance. The results indicate that the desensitization of α4β2 nicotinic receptors with some activation of these receptors may play an important role in improving effects of sazetidine-A on attention.

Keywords

Nicotinic receptors Scopolamine Animal model Cognition 

Notes

Acknowledgments

This study was supported by the NIDA U19 grant DA027990. Georgetown University holds a patent for sazetidine-A.

References

  1. 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
  2. Buccafusco JJ, Beach W, Terry AV Jr (2009) Desensitization of nicotinic acetylcholine receptors as a strategy for drug development. JPET 328:364–370CrossRefGoogle Scholar
  3. Blondel A, Sanger D, Moser P (2000) Characterisation of the effects of nicotine in the five-choice serial reaction task in rats: antagonist studies. Psychopharmacology 149:293–305PubMedCrossRefGoogle Scholar
  4. Bushnell P (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259PubMedCrossRefGoogle Scholar
  5. Bushnell PJ, Oshiro WM, Padnos BK (1997) Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention. Psychopharmacology 134:230–241PubMedCrossRefGoogle Scholar
  6. Carbone AL, Moroni M, Groot-Kormelink PJ, Bermudez I (2009) Pentameric concatenated (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2) nicotine acetylcholine receptors: subunit arrangement determines functional expression. Br J Pharmacol 156:970–981PubMedCrossRefGoogle Scholar
  7. Cincotta SL, Yorek MS, Moschak TM, Lewis SR, Rodefer JS (2008) Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction. Curre Opin Investig Drugs 9:47–56Google Scholar
  8. Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729PubMedCrossRefGoogle Scholar
  9. Dunbar G, Boeijinga PH, Demazieres A, Cisterni C, Kuchibhatla R, Wesnes K, Luthringer R (2007) Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191:919–929PubMedCrossRefGoogle Scholar
  10. Grilly DM (2000) A verification of psychostimulant-induced improvement in sustained attention in rats: effects of d-amphetamine, nicotine, and pemoline. Exp Clin Psychopharmacol 8:14–21PubMedCrossRefGoogle Scholar
  11. 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 117:197–208PubMedCrossRefGoogle Scholar
  12. Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003) Attentional effects of nicotinic agonists in rats. Neuropharmacology 44:1054–1067PubMedCrossRefGoogle Scholar
  13. Hahn B, Shoaib M, Stolerman IP (2011) Selective nicotinic receptor antagonists: effects on attentional and nicotine-induced attentional enhancement. Psychopharmacology 217:75–82PubMedCrossRefGoogle Scholar
  14. Hulme EC, Lu ZL, Saldanha JW, Bee MS (2003) Structure and activation of muscarinic acetylcholine receptors. Biochem Soc Trans 31:29–34PubMedCrossRefGoogle Scholar
  15. Johnson JE, Slade S, Wells C, Petro A, Sexton H, Rezvani AH, Brown ML, Paige MA, McDowell BE, Xiao Y, Kellar KJ, Levin ED (2012) Chronic sazetidine-A infusion reduces nicotine self-administration in male and female rats. Psychopharmacology 222:269–276Google Scholar
  16. Lawrence NS, Ross TJ, Stein EA (2002) Cognitive mechanisms of nicotine on visual attention. Neuron 36:539–548PubMedCrossRefGoogle Scholar
  17. Levin ED, Caldwell DP (2006) Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure. Neurobiol Learn Mem 86:117–122PubMedCrossRefGoogle Scholar
  18. Levin ED, Cauley M, Rezvani AH (2012) Improvement of attentional function with antagonism of nicotinic receptors. Eur J Pharmacol (in press)Google Scholar
  19. Levin ED, Conners CK, Silva D, Canu W, March J (2001) Effects of chronic nicotine and methylphenidate in adults with ADHD. Exp Clin Psychopharmacol 9:83–90PubMedCrossRefGoogle Scholar
  20. Levin ED, Conners CK, Silva D, Hinton SC, Meck WH, March J, Rose JE (1998a) Transdermal nicotine effects on attention. Psychopharmacology 140:135–141PubMedCrossRefGoogle Scholar
  21. Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996a) Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology 123:55–63PubMedCrossRefGoogle Scholar
  22. 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 8:236–242PubMedGoogle Scholar
  23. Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification and anatomic localization. Psychopharmacology 184:523–539PubMedCrossRefGoogle Scholar
  24. Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells D, Hampton D, Petro A, Rose JE, Brown ML, Paige MA, McDowell BE, Kellar K (2010) Sazetidine-A, a selective α4β2 nicotinic receptor desensitizing agent and partial agonist reduces nicotine self-administration in rats. J Pharmacol Exp Ther 332:933–939PubMedCrossRefGoogle Scholar
  25. Levin ED, Simon BB, Conners CK (1998b) Transdermal nicotine treatment of attention deficit/hyperactivity disorder. In: Arneric SP, Brioni JD (eds) Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. Wiley, New York, pp 349–357Google Scholar
  26. Levin ED, Wilson W, Rose JE, McEvoy J (1996b) Nicotine–haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15:429–436PubMedCrossRefGoogle Scholar
  27. Lomazzo E, Hussmann GP, Turner JR, Blendy JA, Rezvani AH, Deguisto DM, Xiao Y1, Levin ED, Perry DC, Kellar K (2011) Effects of sazetidine-A on neuronal nicotinic receptor density in rodent brain. Presented at the 41th Annual Meeting of the Society for Neuroscience, Washington DCGoogle Scholar
  28. 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 144:175–182PubMedCrossRefGoogle Scholar
  29. Mirza NR, Bright JL (2001) Nicotine-induced enhancements in the five-choice serial reaction time task in rats are strain-dependent. Psychopharmacology 154:8–12PubMedCrossRefGoogle Scholar
  30. Mirza NR, Stolerman IP (1998) Nicotine enhances sustained attention in the rat under specific task conditions. Psychopharmacology 138:266–274PubMedCrossRefGoogle Scholar
  31. Mirza NR, Stolerman IP (2000) The role of nicotinic and muscarinic acetylcholine receptors in attention. Psychopharmacology 148:243–250PubMedCrossRefGoogle Scholar
  32. Molchen SE, Mellow AM, Lawlor BA, Weingartner HJ, Cohen RM, Cohen MR, Sunderland T (1990) TRH attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 100:84–89CrossRefGoogle Scholar
  33. 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 118:82–92PubMedCrossRefGoogle Scholar
  34. Newhouse PA, Kellar KP, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED (2012) Transdermal nicotine treatment of mild cognitive impairment: a six-month double-blind pilot clinical trial. Neurology 78:91–101PubMedCrossRefGoogle Scholar
  35. Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36–46PubMedCrossRefGoogle Scholar
  36. Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63:630–638PubMedCrossRefGoogle Scholar
  37. 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 84:329–342PubMedCrossRefGoogle Scholar
  38. Potter AS, Ryan K, Newhouse PA (2009) Effects of acute ultra-low dose mecamylamine on cognition in adult attention-deficit/hyperactivity disorder (ADHD). Hum Psychopharmacol Clin Exp 24:309–317CrossRefGoogle Scholar
  39. Rezvani AH, Bushnell PJ, Levin ED (2002) Nicotine and mecamylamine effects on choice accuracy in an operant signal detection task. Psychopharmacology 164:369–375PubMedCrossRefGoogle Scholar
  40. Rezvani AH, Caldwell DP, Levin ED (2005) Nicotinic–serotonergic drug interactions and attentional performance in rats. Psychopharmacology 179:521–528PubMedCrossRefGoogle Scholar
  41. Rezvani AH, Caldwell DP, Levin ED (2006) Chronic nicotine interactions with clozapine and risperidone and attentional function in rats. Prog Neuropsychopharmacol Biol Psychiatr 30:190–197CrossRefGoogle Scholar
  42. Rezvani AH, Cauley M, Sexton H, Xiao X, Brown ML, Paige MA, McDowell BE, Kellar KL, Levin ED (2011) Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent reverses dizocilpine and scopolamine-induced attentional impairments in rats. Psychopharmacology 215:621–630PubMedCrossRefGoogle Scholar
  43. 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. Progr Neuropsychopharmacol Biol Psychiat 33:269–275CrossRefGoogle Scholar
  44. Rezvani AH, Kholdebarin E, Cauley MM, Levin ED (2009b) Attenuation of pharmacologically-induced attentional impairment by methylphenidate in rats. Pharmacol Biochem Behav 92:141–146PubMedCrossRefGoogle Scholar
  45. Rezvani AH, Kholdebarin E, Dawson E, Levin ED (2008a) Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats. Int J Neuropsychopharmacol 11:63–70PubMedCrossRefGoogle Scholar
  46. Rezvani AH, Levin ED (2001) Cognitive effects of nicotine. Biol Psychiatry 49:258–267PubMedCrossRefGoogle Scholar
  47. Rezvani AH, Levin ED (2003a) Nicotine–alcohol interactions and attentional performance on an operant visual signal detection task in female rats. Pharmacol Biochem Behav 76:75–83PubMedCrossRefGoogle Scholar
  48. Rezvani AH, Levin ED (2003b) Nicotinic–glutamatergic interactions and attentional performance on an operant visual signal detection task in female rats. Eur J Pharmacol 465:83–90PubMedCrossRefGoogle Scholar
  49. Rezvani AH, Levin ED (2004) Nicotine–antipsychotic drug interactions and attentional performance in female rats. Eur J Pharmacol 486:175–182PubMedCrossRefGoogle Scholar
  50. Rezvani AH, Slade S, Wells C, Petro A, Li TK, Lumeng L, Xiao Y, Brown ML, Paige MA, McDowell BE, Kellar KJ, Rose JE, Levin ED (2010) Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent and partial agonist reduces both alcohol and nicotine self-administration in selectively-bred alcohol preferring (P) rats. Psychopharmacology 211:161–174PubMedCrossRefGoogle Scholar
  51. Rezvani AH, Tizabi Y, Getachew B, Hauser SR, Caldwell DP, Hunter C, Levin ED (2008b) Chronic nicotine and dizocilpine effects on nicotinic and NMDA glutamatergic receptor regulation: interactions with clozapine actions and attentional performance in rats. Prog Neuropsychopharmacology Biol Psychiat 32:1030–1040CrossRefGoogle Scholar
  52. Seo SW, Suh MK, Chin J, Na DL (2009) Mental confusion associated with scopolamine patch in elderly with mild cognitive impairment (MCI). Arch Gerontol Geriatr 49:204–207PubMedCrossRefGoogle Scholar
  53. Snedecor GW, Cochran WG (1967) Statistical methods. Iowa State University Press, AmesGoogle Scholar
  54. Stolerman IP, Mirza NR, Hahn B, Shoaib M (2000) Nicotine in an animal model of attention. Eur J Pharmacol 393:147–154PubMedCrossRefGoogle Scholar
  55. Terry AV Jr, Buccafusco JJ, Prendergast MA (1999) Dose-specific improvement in memory-related task performance by rats and aged monkeys administered the nicotinic–cholinergic antagonist mecamylamine. Drug Dev Res 47:127–136CrossRefGoogle Scholar
  56. Terry AV Jr, 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 301:284–292PubMedCrossRefGoogle Scholar
  57. Turchi J, Holley LA, Sarter M (1996) Effects of benzodiazepine receptor inverse agonists and nicotine on behavioral vigilance in senescent rats. J Gerontol A Biol Sci Med Sci 51:B225–B231PubMedCrossRefGoogle Scholar
  58. White HK, Levin ED (1999) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 143:158–165PubMedCrossRefGoogle Scholar
  59. 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. Amer J Psychiat 156:1931–1937PubMedGoogle Scholar
  60. Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, Kellar KJ (2006) Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. Mol Pharmacol 70:1454–1460PubMedCrossRefGoogle Scholar
  61. Xiao Y, Yasuda RP, Sahibzada, Wolfe BB, Horton L, Paige M, Brown ML, Kellar KJ (2010) Sazetidine-A selectively induces a long lasting desensitization of α4β2 nicotinic acetylcholine receptors. Society for Neuroscience 40th Annual Meeting, Washington, DCGoogle Scholar
  62. Xiao Y, Yasuda RP, Sahibzada N, Horton L, DiPietro JR, Iwueze AF, Paige MA, McDowell B, Brown ML, Wolfe BB, Kellar KJ (2008) Pharmacological properties of sazetidine-A, a selective ligand of α4β2 nicotinic acetylcholine receptor. Society for Neuroscience 38th Annual Meeting, Washington, DCGoogle Scholar
  63. 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 29:891–900PubMedCrossRefGoogle Scholar
  64. 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 17:145–155PubMedCrossRefGoogle Scholar
  65. Zarrindast MR (2006) Neurotransmitters and cognition. In: Levin ED (ed) Neurotransmitter interactions and cognitive function. Birkhäuser, Berlin, pp 5–39CrossRefGoogle Scholar
  66. Zwart R, Carbone AL, Moroni M, Bermudez I, Mogg AJ, Folly EA, Broad LM, Williams AC, Zhang D, Ding C, Heinz BA, Sher E (2008) Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors. Mol Pharmacol 73:1838–1843PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Amir H. Rezvani
    • 1
  • Marty Cauley
    • 1
  • Yingxian Xiao
    • 2
  • Kenneth J. Kellar
    • 2
  • Edward D. Levin
    • 1
  1. 1.Department of PsychiatryDuke University Medical CenterDurhamUSA
  2. 2.Department of Pharmacology and PhysiologyGeorgetown UniversityWashingtonUSA

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