Skip to main content
SpringerLink
Log in

Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague–Dawley rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of α4β2 nicotinic receptors in sustained attention using a novel selective α4β2 nicotinic receptor ligand, sazetidine-A.

Methods

Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination.

Results

Percent hit and percent correct rejection showed that dizocilpine caused significant (p < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly (p < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant (p < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly (p < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration.

Conclusions

These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • 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 219–232

    Google Scholar 

  • 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 149:293–305

    Article  PubMed  CAS  Google Scholar 

  • Buccafusco JJ, Brach JW, Terry AV (2009) Desensitization of nicotinic acetylcholine receptors as a stategy for drug development. J Pharmacol Exp Ther 328:364–370

    Article  PubMed  CAS  Google Scholar 

  • Bushnell P (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259

    Article  PubMed  CAS  Google Scholar 

  • 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 134:230–241

    Article  PubMed  CAS  Google Scholar 

  • Cannady R, Weir R, Wee B, Gotschlich E, Kolia N, Lau E, Brotherton J, Levin ED (2009) Nicotinic antagonist effects in the mediodorsal thalamic nucleus: regional heterogeneity of nicotinic receptor involvement in cognitive function. Biochem Pharmacol 78:788–794

    Article  PubMed  CAS  Google Scholar 

  • Carbone AL, Moroni M, Groot-Kormelink PJ, Bermudez I (2009) Pentameric concatenated (a4)2(b2)3 and (a4)3(b2)2 nicotinic acetylcholine receptors: subunit arrangement determines functional expression. Br J Pharmacol 156:970–981

    Article  PubMed  CAS  Google Scholar 

  • Collins AC, Romm E, Wehner JM (1988) Nicotine tolerance: an analysis of the time course of its development and loss in the rat. Psychopharmacology 96:7–14

    Article  PubMed  CAS  Google Scholar 

  • Deiana S, Harrington CR, Wischik CM, Riedel G (2009) Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology 202:53–65

    Article  PubMed  CAS  Google Scholar 

  • Ellis JR, Ellis KA, Barthoolomeusz CF, Harrisn BJ, Wensens KA, Erskine FF, Vitetta L, Nathan PJ (2006) Muscarinic and nicotinic recptors synergistically modulate working memory and attention in humans. Int J Neuropsychopharmacol 9:175–189

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Grottick AJ, Haman M, Wyler R, Higgins GA (2003) Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands. Neuropsychopharmacology 28:880–887

    PubMed  CAS  Google Scholar 

  • Hahn B, Ross TJ, TYang Y, Kim I, Huestis MA, Stein EA (2007) Nicotine enhances visuospatial attention by deactivating areas of resting brain default network. J Neurosci 27:3477–3489

    Article  PubMed  CAS  Google Scholar 

  • Hahn B, Ross TJ, Wolkenberg FA, Shakleya DM, Huestis MA, Stein EA (2009) Performace effects of nicotine during selective attention, divided attention, and simple stimulus detection: an fMRI study. Cereb Cortex 19:1990–2000

    Article  PubMed  Google Scholar 

  • Hashimoto K, Koike K, Shimizu E, Iyo M (2005) Alpha7 nicotinic receptor agonists as potential therapeutic drugs for schizophrenia. Curr Med Chem Cent Nerv Syst Agents 5:171–184

    Article  CAS  Google Scholar 

  • Hasselmo ME, Sarter M (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacol Rev 36:52–73

    Article  CAS  Google Scholar 

  • Howe WM, Ji J, Parikh V, Williams S, Mocaër E, Trocmé-Thiberge C, Sarter M (2010) Enhancement of attentional performance by selective stimulation os alpha4beta2* nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35:1391–1401

    Article  PubMed  CAS  Google Scholar 

  • Hulihan-Giblin BA, Lumpkin MD, Kellar KJ (1990) Acute effects of nicotine on prolactin release in the rat: agonist and antagonist effects of a single injection of nicotine. J Pharmacol Exp Ther 252:15–20

    PubMed  CAS  Google Scholar 

  • Hulme EC, Lu ZL, Saldanha JW, Bee MS (2003) Structure and activation of muscarinic acetylcholine receptors. Biochem Soc Trans 31:29–34

    Article  PubMed  CAS  Google Scholar 

  • Katz B, Thesleff S (1957) On the factors which determine the amplitude of the miniature end-plate potential. J Physiol 137:267–278

    PubMed  CAS  Google Scholar 

  • Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, Nakazato M, Okamura N, Stevens KE, Freedman R, Iyo M (2005) Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 76:67–72

    Article  PubMed  Google Scholar 

  • Langley JH, Dickenson WL (1889) On the local paralysis of the peripheral ganglia and on the connexion of different classes of nerve fibres with them. Proc R Soc 46:423–431

    Article  Google Scholar 

  • Lawrence NS, Ross TJ, Stein EA (2002) Cognitive mechanisms of nicotine on visual attention. Neuron 36:539–548

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Caldwell DP (2006) Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure. Neurobiol Learn Mem 86:117–122

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Christopher NC (2002) Persistence of nicotinic agonist RJR 2403 induced working memory improvement in rats. Drug Dev Res 55:97–103

    Article  CAS  Google Scholar 

  • Levin ED, Briggs SJ, Christopher NC, Rose JE (1993) Chronic nicotinic stimulation and blockade effects on working memory. Behav Pharmacol 4:179–182

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Levin ED, Conners CK, Silva D, Hinton SC, Meck WH, March J, Rose JE (1998) Transdermal nicotine effects on attention. Psychopharmacology 140:135–141

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Bettegowda C, Blosser J, Gordon J (1999) AR-R17779, an α7 nicotinic agonist, improves learning and memory in rats. Behav Pharmacol 10:675–680

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification and anatomic localization. Psychopharmacology 184:523–539

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Rezvani AH, Slade S, Cauley M, Wells D, Hampton D, Petro A, Rose JE, Xiao Y, 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 332:933–939

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Marks MJ, Meinerz NM, Brown RW, Collins AC (2010) 86Rb + efflux mediated by a4b2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization. Biochem Pharmacol 80:1238–1251

    Article  PubMed  CAS  Google Scholar 

  • Martin LF, Kem WR, Freedman R (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology 174:54–64

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Mirza NR, Stolerman IP (1998) Nicotine enhances sustained attention in the rat under specific task conditions. Psychopharmacology 138:266–274

    Article  PubMed  CAS  Google Scholar 

  • Mirza NR, Stolerman IP (2000) The role of nicotinic and muscarinic acetylcholine receptors in attention. Psychopharmacology 148:243–250

    Article  PubMed  CAS  Google Scholar 

  • Molchen SE, Mellow AM, Lawlor BA, Weingartner HJ, Cohen RM, Cohen MR, Sunderland T (1990) TRH attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 100:84–89

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36–46

    Article  PubMed  CAS  Google Scholar 

  • 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 63:630–638

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Rezvani AH, Levin ED (2003) Nicotinic–glutamatergic interactions and attentional performance on an operant visual signal detection task in female rats. Eur J Pharmacol 465:83–90

    Article  PubMed  CAS  Google Scholar 

  • Rezvani AH, Levin ED (2004) Nicotine–antipsychotic drug interactions and attentional performance in female rats. Eur J Pharmacol 486:175–182

    Article  PubMed  CAS  Google Scholar 

  • Rezvani AH, Bushnell PJ, Levin ED (2002) Nicotine and mecamylamine effects on choice accuracy in an operant signal detection task. Psychopharmacology 164:369–375

    Article  PubMed  CAS  Google Scholar 

  • Rezvani AH, Caldwell P, Levin ED (2005) Nicotinic-serotonergic drug interactions and attentional performance in rats. Psychopharmacology: 179:521–528

  • Rezvani AH, Caldwell DP, Levin ED (2006) Chronic nicotine interactions with clozapine and risperidone and attentional function in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 30:190–197

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED (2009) 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

    Article  PubMed  CAS  Google Scholar 

  • 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 211:161–174

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Parikh V, Howe WM (2009) nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms. Biochem Pharmacol 78:658–667

    Article  PubMed  CAS  Google Scholar 

  • 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 49:204–207

    Article  PubMed  CAS  Google Scholar 

  • Stolerman IP, Mirza NR, Hahn B, Shoaib M (2000) Nicotine in an animal model of attention. Eur J Pharmacol 393:147–154

    Article  PubMed  CAS  Google Scholar 

  • Sydserff S, Sutton EJ, Song D, Quirk MC, Maciag C, Li C, Jonak G, Gurley D, Gordon JC, Christian EP, Doherty JJ, Hudzik T, Johnson E, Mrzljak L, Piser T, Smagin GN, Wang Y, Widzowski D, Smith JS (2009) Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochem Pharmacol 78:880–888

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Turchi J, Holley LA, Sarter M (1995) Effects of nicotinic acetylcholine receptor ligands on behavioral vigilance in rats. Psychopharmacology 118:195–205

    Article  PubMed  CAS  Google Scholar 

  • Warburton DM, Brown K (1971) Attenuation of stimulus sensitivity induced by scopolamine. Nature 230:126–127

    Article  PubMed  CAS  Google Scholar 

  • 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 70:1454–1460

    Article  PubMed  CAS  Google Scholar 

  • 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 receptors. Proceedings of the 38th Annual Meeting of the Society for Neuroscience, Washington, DC

  • Xiao Y, Yasuda RP, Sahibzada N, Wolfe BB, Horton L, Paige M, Brown ML, Kellar KJ (2010) Sazetidine-A selectively induces a long-lasting desensitization of α4β2 nAChRs. Proceedings of the 4oth Annual Meeting of the Society for Neurosciences, San Diego

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 73:1838–1843

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study was supported by NIDA grant DA027990. Georgetown University holds patent rights for sazetidine-A, and Drs. Kellar and Xiao are two of the inventors on this patent.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC, 27710, USA

    Amir H. Rezvani, Marty Cauley, Hannah Sexton & Edward D. Levin

  2. Department of Pharmacology, Georgetown University School of Medicine, Washington, DC, USA

    Yingxian Xiao & Kenneth J. Kellar

  3. Drug Discovery Program, Georgetown University School of Medicine, Washington, DC, USA

    Milton L. Brown, Mikell A. Paige & Brian E. McDowell

Authors
  1. Amir H. Rezvani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marty Cauley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hannah Sexton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingxian Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Milton L. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mikell A. Paige
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Brian E. McDowell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenneth J. Kellar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Edward D. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amir H. Rezvani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rezvani, A.H., Cauley, M., Sexton, H. et al. 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 (2011). https://doi.org/10.1007/s00213-010-2161-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-2161-8

Keywords

Search

Navigation