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.
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References
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
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
Aquila R, Citrome L (2015) Cognitive impairment in schizophrenia: the great unmet need. CNS Spectr 20:32–40. doi:10.1017/S109285291500070X
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
Bisset WI, Butler AR, Glidewell C, Reglinski J (1981) Sodium nitroprusside and cyanide release: reasons for re-appraisal. Br J Anaesth 53:1015–1018
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
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
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
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, 53
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 107:243–254
Coyle JT (2012) NMDA receptor and schizophrenia: a brief history. Schizophr Bull 38:920–926. doi:10.1093/schbul/sbs076
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
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
Fleming K, Goldberg TE, Gold JM, Weinberger DR (1995) Verbal working memory dysfunction in schizophrenia: use of a Brown-Peterson paradigm. Psychiatry Res 56:155–161
Friederich JA, Butterworth JF (1995) Sodium nitroprusside: twenty years and counting. Anesth Analg 81:152–162
Gattaz WF, Cramer H, Beckmann H (1983) Low CSF concentrations of cyclic GMP in schizophrenia. Br J Psychiatry J Ment Sci 142:288–291
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
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
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
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
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
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
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
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 51:199–214
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
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
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
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
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
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
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
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
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
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
Martinelli C, Shergill SS (2015) Clarifying the role of pattern separation in schizophrenia: the role of recognition and visual discrimination deficits. Schizophr Res 166:328–333
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
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
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
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
Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169. doi:10.1038/nn.2647
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
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 21:283–289
Palmer BW, Heaton RK, Paulsen JS et al (1997) Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 11:437–446
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
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
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
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
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
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
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
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
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
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.
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Hurtubise, J.L., Marks, W.N., Davies, D.A. et al. MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside. Psychopharmacology 234, 211–222 (2017). https://doi.org/10.1007/s00213-016-4451-2
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DOI: https://doi.org/10.1007/s00213-016-4451-2