Advertisement

Psychopharmacology

, Volume 234, Issue 2, pp 211–222 | Cite as

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

  • Jessica L. Hurtubise
  • Wendie N. Marks
  • Don A. Davies
  • Jillian K. Catton
  • Glen B. Baker
  • John G. HowlandEmail author
Original Investigation

Abstract

Rationale

The cognitive symptoms observed in schizophrenia are not consistently alleviated by conventional antipsychotics. Following a recent pilot study, sodium nitroprusside (SNP) has been identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.

Objective

The present experiments were designed to explore the effects of SNP on the highly translatable trial-unique, delayed nonmatching-to-location (TUNL) task in rats with and without acute MK-801 treatment.

Methods

SNP (0.5, 1.0, 2.0, 4.0, and 5.0 mg/kg) and MK-801 (0.05, 0.075, and 0.1 mg/kg) were acutely administered to rats trained on the TUNL task.

Results

Acute MK-801 treatment impaired TUNL task accuracy. Administration of SNP (2.0 mg/kg) with MK-801 (0.1 mg/kg) failed to rescue performance on TUNL. SNP (5.0 mg/kg) administration nearly 4 h prior to MK-801 (0.05 mg/kg) treatment had no preventative effect on performance impairments. SNP (2.0 mg/kg) improved performance on a subset of trials.

Conclusion

These results suggest that SNP may possess intrinsic cognitive-enhancing properties but is unable to block the effects of acute MK-801 treatment on the TUNL task. These results are inconsistent with the effectiveness of SNP as an adjunct therapy for working memory impairments in schizophrenia patients. Future studies in rodents that assess SNP as an adjunct therapy will be valuable in understanding the mechanisms underlying the effectiveness of SNP as a treatment for schizophrenia.

Keywords

Schizophrenia NMDA receptor Nitric oxide donor Working memory Pattern separation 

Notes

Acknowledgments

This research was supported by an operating grant from the Canadian Institutes for Health Research (CIHR; #125984) and a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). JGH is a CIHR New Investigator. JLH and WNM received salary support from the College of Medicine at the University of Saskatchewan. GBB received salary support and grant funding from the University of Alberta.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Adell A, Jimenez-Sanchez L, Lopez-Gil X, Romon T (2012) Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bull 38:9–14. doi: 10.1093/schbul/sbr133 CrossRefPubMedGoogle Scholar
  2. Adler CM, Malhotra AK, Elman I et al (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649. doi: 10.1176/ajp.156.10.1646 CrossRefPubMedGoogle Scholar
  3. Aquila R, Citrome L (2015) Cognitive impairment in schizophrenia: the great unmet need. CNS Spectr 20:32–40. doi: 10.1017/S109285291500070X CrossRefGoogle Scholar
  4. Bhagyavathi HD, Mehta UM, Thirthalli J et al (2015) Cascading and combined effects of cognitive deficits and residual symptoms on functional outcome in schizophrenia—a path-analytical approach. Psychiatry Res 229:264–271. doi: 10.1016/j.psychres.2015.07.022 CrossRefPubMedGoogle Scholar
  5. Bisset WI, Butler AR, Glidewell C, Reglinski J (1981) Sodium nitroprusside and cyanide release: reasons for re-appraisal. Br J Anaesth 53:1015–1018CrossRefPubMedGoogle Scholar
  6. Bozikas VP, Kosmidis MH, Kioperlidou K, Karavatos A (2004) Relationship between psychopathology and cognitive functioning in schizophrenia. Compr Psychiatry 45:392–400. doi: 10.1016/j.comppsych.2004.03.006 CrossRefPubMedGoogle Scholar
  7. Bujas-Bobanovic M, Bird DC, Robertson HA, Dursun SM (2000) Blockade of phencyclidine-induced effects by a nitric oxide donor. Br J Pharmacol 130:1005–1012. doi: 10.1038/sj.bjp.0703406 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bussey TJ, Holmes A, Lyon L et al (2012) New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. Neuropharmacology 62:1191–1203. doi: 10.1016/j.neuropharm.2011.04.011 CrossRefPubMedGoogle Scholar
  9. Carbon M, Correll CU (2014) Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr 19(Suppl 1):38–52 . doi: 10.1017/S1092852914000601quiz 35–37, 53PubMedGoogle Scholar
  10. Cohn J, Ziriax JM, Cox C, Cory-Slechta DA (1992) Comparison of error patterns produced by scopolamine and MK-801 on repeated acquisition and transition baselines. Psychopharmacology 107:243–254CrossRefPubMedGoogle Scholar
  11. Coyle JT (2012) NMDA receptor and schizophrenia: a brief history. Schizophr Bull 38:920–926. doi: 10.1093/schbul/sbs076 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Das T, Ivleva EI, Wagner AD et al (2014) Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr Res 159:193–197. doi: 10.1016/j.schres.2014.05.006 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Fatouros-Bergman H, Cervenka S, Flyckt L et al (2014) Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia. Schizophr Res 158:156–162. doi: 10.1016/j.schres.2014.06.034 CrossRefPubMedGoogle Scholar
  14. Fleming K, Goldberg TE, Gold JM, Weinberger DR (1995) Verbal working memory dysfunction in schizophrenia: use of a Brown-Peterson paradigm. Psychiatry Res 56:155–161CrossRefPubMedGoogle Scholar
  15. Friederich JA, Butterworth JF (1995) Sodium nitroprusside: twenty years and counting. Anesth Analg 81:152–162PubMedGoogle Scholar
  16. Gattaz WF, Cramer H, Beckmann H (1983) Low CSF concentrations of cyclic GMP in schizophrenia. Br J Psychiatry J Ment Sci 142:288–291CrossRefGoogle Scholar
  17. Gourgiotis I, Kampouri NG, Koulouri V et al (2012) Nitric oxide modulates apomorphine-induced recognition memory deficits in rats. Pharmacol Biochem Behav 102:507–514. doi: 10.1016/j.pbb.2012.06.013 CrossRefPubMedGoogle Scholar
  18. Greene R (2001) Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577. doi: 10.1002/hipo.1072 CrossRefPubMedGoogle Scholar
  19. Hallak JEC, Maia-de-Oliveira JP, Abrao J et al (2013) Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. JAMA Psychiatry 70:668–676. doi: 10.1001/jamapsychiatry.2013.1292 CrossRefPubMedGoogle Scholar
  20. Hoirisch-Clapauch S, Nardi A (2015) Improvement of psychotic symptoms and the role of tissue plasminogen activator. Int J Mol Sci 16:27550–27560. doi: 10.3390/ijms161126053 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hottinger DG, Beebe DS, Kozhimannil T et al (2014) Sodium nitroprusside in 2014: A clinical concepts review. J Anaesthesiol Clin Pharmacol 30:462–471. doi: 10.4103/0970-9185.142799 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kandratavicius L, Balista P, Wolf D et al (2015) Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia. BMC Neurosci 16. doi: 10.1186/s12868-015-0149-3
  23. Kim J, Glahn DC, Nuechterlein KH, Cannon TD (2004) Maintenance and manipulation of information in schizophrenia: further evidence for impairment in the central executive component of working memory. Schizophr Res 68:173–187. doi: 10.1016/S0920-9964(03)00150-6 CrossRefPubMedGoogle Scholar
  24. Krystal JH, Karper LP, Seibyl JP et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214CrossRefPubMedGoogle Scholar
  25. Kumar G, Olley J, Steckler T, Talpos J (2015) Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation. Psychopharmacology 232:3991–4003. doi: 10.1007/s00213-015-4008-9 CrossRefPubMedGoogle Scholar
  26. Lee J, Park S (2005) Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol 114:599–611. doi: 10.1037/0021-843X.114.4.599 CrossRefPubMedGoogle Scholar
  27. Lins BR, Howland JG (2016) Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers. Behav Brain Res 301:152–160. doi: 10.1016/j.bbr.2015.12.029 CrossRefPubMedGoogle Scholar
  28. Lins BR, Phillips AG, Howland JG (2015) Effects of D- and L-govadine on the disruption of touchscreen object-location paired associates learning in rats by acute MK-801 treatment. Psychopharmacology 232:4371–4382. doi: 10.1007/s00213-015-4064-1 CrossRefPubMedGoogle Scholar
  29. Maia-de-Oliveira JP, Lobão-Soares B, Baker GB et al (2014) Sodium nitroprusside, a nitric oxide donor for novel treatment of schizophrenia, may also modulate dopaminergic systems. Schizophr Res 159:558–559. doi: 10.1016/j.schres.2014.08.020 CrossRefPubMedGoogle Scholar
  30. Maia-de-Oliveira JP, Abrao J, Evora PR et al (2015a) The effects of sodium nitroprusside treatment on cognitive deficits in schizophrenia: a pilot study. J Clin Psychopharmacol 35:83–85. doi: 10.1097/JCP.0000000000000258 CrossRefPubMedGoogle Scholar
  31. Maia-de-Oliveira JP, Lobão-Soares B, Ramalho T et al (2015b) Nitroprusside single-dose prevents the psychosis-like behavior induced by ketamine in rats for up to one week. Schizophr Res 162:211–215. doi: 10.1016/j.schres.2014.12.035 CrossRefPubMedGoogle Scholar
  32. Malhotra MDA (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150. doi: 10.1016/S0893-133X(97)00036-5 CrossRefPubMedGoogle Scholar
  33. Marder SR, Fenton W (2004) Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res 72:5–9. doi: 10.1016/j.schres.2004.09.010 CrossRefPubMedGoogle Scholar
  34. Markou A, Chiamulera C, Geyer MA et al (2009) Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 34:74–89. doi: 10.1038/npp.2008.173 CrossRefPubMedGoogle Scholar
  35. Martinelli C, Shergill SS (2015) Clarifying the role of pattern separation in schizophrenia: the role of recognition and visual discrimination deficits. Schizophr Res 166:328–333CrossRefPubMedGoogle Scholar
  36. McAllister KAL, Saksida LM, Bussey TJ (2013) Dissociation between memory retention across a delay and pattern separation following medial prefrontal cortex lesions in the touchscreen TUNL task. Neurobiol Learn Mem 101:120–126. doi: 10.1016/j.nlm.2013.01.010 CrossRefPubMedPubMedCentralGoogle Scholar
  37. McGrath J, Saha S, Chant D, Welham J (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76. doi: 10.1093/epirev/mxn001 CrossRefPubMedGoogle Scholar
  38. Mesholam-Gately RI, Giuliano AJ, Goff KP et al (2009) Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23:315–336. doi: 10.1037/a0014708 CrossRefPubMedGoogle Scholar
  39. Moghaddam B, Krystal JH (2012) Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 38:942–949. doi: 10.1093/schbul/sbs075 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169. doi: 10.1038/nn.2647 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Oomen CA, Hvoslef-Eide M, Heath CJ et al (2013) The touchscreen operant platform for testing working memory and pattern separation in rats and mice. Nat Protoc 8:2006–2021. doi: 10.1038/nprot.2013.124 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Ortuño F, Arbizu J, Soutullo CA, Bonelli RM (2009) Is there a cortical blood flow redistribution pattern related with perseverative error in schizophrenia? Psychiatr Danub 21:283–289PubMedGoogle Scholar
  43. Palmer BW, Heaton RK, Paulsen JS et al (1997) Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 11:437–446CrossRefPubMedGoogle Scholar
  44. Perrin MA, Butler PD, DiCostanzo J et al (2010) Spatial localization deficits and auditory cortical dysfunction in schizophrenia. Schizophr Res 124:161–168. doi: 10.1016/j.schres.2010.06.004 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Soria Bauser D, Thoma P, Aizenberg V et al (2012) Face and body perception in schizophrenia: a configural processing deficit? Psychiatry Res 195:9–17. doi: 10.1016/j.psychres.2011.07.017 CrossRefPubMedGoogle Scholar
  46. Svensson M, Grahm M, Ekstrand J et al (2015) Effect of electroconvulsive seizures on pattern separation: ECS, neurogenesis, and pattern separation. Hippocampus 25:1351–1360. doi: 10.1002/hipo.22441 CrossRefPubMedGoogle Scholar
  47. Szoke A, Meary A, Trandafir A et al (2008) Executive deficits in psychotic and bipolar disorders – implications for our understanding of schizoaffective disorder. Eur Psychiatry 23:20–25. doi: 10.1016/j.eurpsy.2007.10.006 CrossRefPubMedGoogle Scholar
  48. Talpos JC, McTighe SM, Dias R et al (2010) Trial-unique, delayed nonmatching-to-location (TUNL): a novel, highly hippocampus-dependent automated touchscreen test of location memory and pattern separation. Neurobiol Learn Mem 94:341–352. doi: 10.1016/j.nlm.2010.07.006 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Talpos JC, Fletcher AC, Circelli C et al (2012) The pharmacological sensitivity of a touchscreen-based visual discrimination task in the rat using simple and perceptually challenging stimuli. Psychopharmacology 221:437–449. doi: 10.1007/s00213-011-2590-z CrossRefPubMedGoogle Scholar
  50. Trevlopoulou A, Touzlatzi N, Pitsikas N (2016) The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats. Psychopharmacology 233:1045–1054. doi: 10.1007/s00213-015-4181-x CrossRefPubMedGoogle Scholar
  51. Tuplin EW, Stocco MR, Holahan MR (2015) Attenuation of MK-801-induced behavioral perseveration by typical and atypical antipsychotic pretreatment in rats. Behav Neurosci 129:399–411. doi: 10.1037/bne0000066 CrossRefPubMedGoogle Scholar
  52. Vingerhoets WAM, Bloemen OJN, Bakker G, van Amelsvoort TAMJ (2013) Pharmacological interventions for the MATRICS cognitive domains in schizophrenia: what’s the evidence? Front Psychiatry. doi: 10.3389/fpsyt.2013.00157 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jessica L. Hurtubise
    • 1
  • Wendie N. Marks
    • 1
  • Don A. Davies
    • 1
  • Jillian K. Catton
    • 1
  • Glen B. Baker
    • 2
  • John G. Howland
    • 1
    Email author
  1. 1.Department of PhysiologyUniversity of SaskatchewanSaskatoonCanada
  2. 2.Department of Psychiatry (NRU)University of AlbertaEdmontonCanada

Personalised recommendations