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Crocins, the active constituents of Crocus Sativus L., counteracted ketamine–induced behavioural deficits in rats

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Abstract

Rationale

Experimental evidence indicates that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders including anxiety and depression.

Objectives

The present study was designed to investigate the ability of crocins to counteract schizophrenia-like behavioural deficits produced by ketamine in rats.

Methods

Crocin’s ability to counteract hypermotility, stereotypies and ataxia induced by ketamine was evaluated in a motor activity cage. The ability of crocins to reverse ketamine-induced memory deficits was assessed using the novel object recognition task (NORT). The social interaction test was used in order to examine the effects of crocins on ketamine-induced social withdrawal.

Results

Crocins (50 but not 30 mg/kg, i.p.) attenuated ketamine (25 mg/kg, i.p.)-induced hypermotility, stereotypies and ataxia. In a subsequent study, post-training administration of crocins (15 and 30 mg/kg, i.p.) reversed ketamine (3 mg/kg, i.p.)-induced performance deficits in the NORT. Finally, crocins (50 but not 30 mg/kg, i.p.) counteracted the ketamine (8 mg/kg, i.p.)-induced social isolation in the social interaction test.

Conclusions

Our findings show that crocins attenuated schizophrenia-like behavioural deficits induced by the non-competitive NMDA receptor antagonist ketamine in rats.

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References

  • Ahmad AS, Ansari MA, Ahmad M, Saleem S, Yousuf S, Hoda MN, Islam F (2005) Neuroprotection by crocetin in a hemi-parkinsonian rat model. Pharmacol Biochem Behav 81:805–813

    Article  CAS  PubMed  Google Scholar 

  • Akhondzabeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F (2004) Comparison of Crocus sativus L., and imipramine in the treatment of mild to moderate depression: a pilot double-blind, randomized trial. Complement Altern Med 4:12–16

    Article  Google Scholar 

  • Andine P, Widermark N, Axelsson R, Nyberg G, Olofsson U, Martensson E, Sandberg M (1999) Characterization of MK-801-induced behavior as putative rat model of psychosis. J Pharmacol Exp Ther 290:1393–1408

    CAS  PubMed  Google Scholar 

  • Bartolini L, Casamenti F, Pepeu G (1996) Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions. Pharmacol Biochem Behav 53:277–283

    Article  CAS  PubMed  Google Scholar 

  • Berger F, Hensel A, Nieber K (2011) Saffron extracts and trans-crocetin inhibit glutamatergic synptic transmission in rat cortical brain slices. Neuroscience 180:238–247

    Article  CAS  PubMed  Google Scholar 

  • Bitanihirwe BK, Woo TU (2011) Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 35:878–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boultadakis A, Pitsikas N (2010) Effects of the nitric oxide inhibitor L-NAME on recognition and spatial memory deficits produced by different NMDA receptor antagonists in the rat. Neuropsychopharmacology 35:2357–2366

    Article  CAS  PubMed  Google Scholar 

  • Calev A, Venables PH, Monk AF (1983) Evidence for distinct verbal memory pathologies in severely and mildly disturbed schizophrenics. Schizophr Bull 9:247–264

    Article  CAS  PubMed  Google Scholar 

  • Cavoy A, Delacour J (1993) Spatial but not object recognition is impaired by aging in rats. Physiol Behav 53:527–530

    Article  CAS  PubMed  Google Scholar 

  • de Lima MNM, Presti-Torres J, Dornelles A, Scalco SF, Roesler R, Garcia VA, Schroeder N (2011) Modulatory influence of dopamine receptors on consolidation of object recognition memory. Neurobiol Learn Mem 95:305–310

    Article  PubMed  Google Scholar 

  • de Oliveira L, Spiazzi CM, Bortolin T, Canever L, Petronilho F, Mina FG, Dal-Pizzol F, Quevedo J, Zugno AI (2009) Different sub-anesthetic doses of ketamine increase oxidative stress in the brain of rats. Prog Neuropsychopharmacol Biol Psychiatry 33:1003–1008

    Article  PubMed  Google Scholar 

  • del Campo CP, Carmona M, Maggi L, Kanakis CD, Anastasaki EG, Tarantilis PA, Polissiou MG, Alonso GL (2010) Effects of mild temperature conditions during dehydration procedures on saffron quality parameters. J Sci Food Agric 90:719–725

    PubMed  Google Scholar 

  • Dere E, Huston JP, De Souza Silva MA (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 31:673–704

    Article  CAS  PubMed  Google Scholar 

  • Edwards J, Jackson HJ, Pattison PE (2002) Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clin Psychol Rev 22:789–832

    Article  PubMed  Google Scholar 

  • Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data. Behav Brain Res 31:47–59

    Article  CAS  PubMed  Google Scholar 

  • Field JR, Walker AG, Conn PJ (2011) Targeting glutamate synapses in schizophrenia. Trends Mol Med 17:689–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freedman R (2003) Schizophrenia. N Engl J Med 349:1738–1749

    Article  CAS  PubMed  Google Scholar 

  • Georgiadou G, Tarantilis PA, Pitsikas N (2012) Effects of the active constituents of Crocus Sativus L, crocins in an animal model of obsessive-compulsive disorder. Neurosci Lett 528:27–30

    Article  CAS  PubMed  Google Scholar 

  • Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology, the fourth generation of progress. Raven, New York, pp 787–798

  • Ghadrdoost B, Ali Vafaei A, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlvan S (2011) Protective effect of saffron extracts and its active constituents crocins against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 667:222–229

    Article  CAS  PubMed  Google Scholar 

  • Hosseinzadeh H, Khosravan V (2005) Anticonvulsant effects of aqueous and ethanolic extracts of Crocus Sativus L., stigmas in mice. Arch Iran Med 5:44–47

    Google Scholar 

  • Hosseinzadeh H, Sadeghnia HR (2007) Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of the GABAergic and opioids systems. Phytomedicine 14:256–262

    Article  CAS  PubMed  Google Scholar 

  • Hosseinzadeh H, Sadeghnia HR, Rahimi A (2008) Effects of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic acid treatment in anesthetized rats. Planta Med 74:1441–1445

    Article  CAS  PubMed  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    CAS  PubMed  Google Scholar 

  • Kanakis CD, Daferera DJ, Tarantilis PA, Polissiou MG (2004) Qualitative determination of volatile compounds and quantitative evaluation of safranal and 4-hydroxy-2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde. J Agric Food Chem 52:4515–4521

    Article  CAS  PubMed  Google Scholar 

  • Kanakis CD, Tarantilis PA, Tajmir-Riahi A, Polissiou MG (2007) DNA interaction with saffron’s secondary metabolites safranal, crocetin, and dimethylcrocetin. DNA Cell Biol 26:63–70

    Article  CAS  PubMed  Google Scholar 

  • Koros E, Rosenbrock H, Birk G, Weiss C, Sams-Dodd F (2007) The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 32:562–576

    Article  CAS  PubMed  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremmer JD, Heninger GR, Bowers MB Jr, Chamey DS (1994) Sub-anesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    Article  CAS  PubMed  Google Scholar 

  • Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467

    Article  CAS  PubMed  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    Article  CAS  PubMed  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effcts by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic transmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    CAS  PubMed  Google Scholar 

  • Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV (2004) Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology 29:208–218

    Article  CAS  PubMed  Google Scholar 

  • Naghizadeh B, Boroushaki MT, Vahdati Mashhadian N, Mansouri MT (2008) Protective effects of crocins against cisplatin-induced acute renal failure and oxidative stress in rats. Iran Biomed J 12:93–100

    CAS  PubMed  Google Scholar 

  • Noorbala AA, Akhondzabeh S, Tahmacebi-Pour N, Jamshidi AH (2005) Hydro-alcoholic extract of Crocus sativus L., versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized trial. J Ethnopharmacol 97:281–284

    Article  CAS  PubMed  Google Scholar 

  • Ochiai T, Soeda S, Ohno S, Tanaka H, Shoyama Y, Shimeno H (2004) Crocins prevent the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing gluthathione synthesis. Neurochem Int 44:321–330

    Article  CAS  PubMed  Google Scholar 

  • O’Shea M, McGregor IS, Mallet PE (2006) Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats. J Psychopharmacol 20:611–621

    Article  PubMed  Google Scholar 

  • Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margariti M, Lamari FN (2006) Inhibitory activity of amyloid-β aggregation and antioxidant properties of Crocus sativus extract and its crocins constituents. J Agric Food Chem 54:8762–8768

    Article  CAS  PubMed  Google Scholar 

  • Pitsikas N, Sakellaridis N (2006) Crocus Sativus L. extracts antagonize memory impairments in different behavioural tasks in the rat. Behav Brain Res 173:112–115

    Article  PubMed  Google Scholar 

  • Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N (2007) Effects of the active constituents of Crocus sativus L., crocins on recognition and spatial rats’ memory. Behav Brain Res 183:141–146

    Article  CAS  PubMed  Google Scholar 

  • Pitsikas N, Boultadakis A, Georgiadou G, Tarantilis PA, Sakellaridis N (2008) Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of anxiety. Phytomedicine 15:1135–1139

    Article  CAS  PubMed  Google Scholar 

  • Razoux F, Garcia R, Lena I (2007) Ketamine at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology 32:719–727

    Article  CAS  PubMed  Google Scholar 

  • Reddy RD, Yao JK (1996) Free radical pathology in schizophrenia: a review. Prostaglandins. Luk Essent Fatty Acids 55:33–43

    Article  CAS  Google Scholar 

  • Rios JL, Recio MC, Ginger RM, Manz S (1996) An update review of saffron and its active constituents. Phytother Res 10:189–193

    Article  CAS  Google Scholar 

  • Robbins TW (1977) Critique of the methods available for the measurement of spontaneous motor activity. In: Iversen SD, Iversen LL, Snyder SH (eds) Handbook of psychopharmacology. Plenum Press, New York

    Google Scholar 

  • Sams-Dodd F (1995) Automation of the social interaction test by video-tracking system: behavioural effects of repeated phencyclidine treatment. J Neurosci Methods 59:157–167

    Article  CAS  PubMed  Google Scholar 

  • Sams-Dodd F (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7:3–23

    CAS  PubMed  Google Scholar 

  • Smith JW, Gastambide F, Gilmour G, Dix S, Foss J, Lloyd K, Malik N, Tricklebank M (2011) A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodents assays of attention and working memory. Psychopharmacology 217:255–269

    Article  CAS  PubMed  Google Scholar 

  • Sugiura M, Shoyama Y, Saito H, Abe K (1994) Crocin (crocetin digentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. J Pharmacol Exp Ther 271:703–707

    CAS  PubMed  Google Scholar 

  • Sugiura M, Shoyama Y, Saito H, Nishiyama N (1995) Crocin improves the ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks. Proc Jpn Acad 71:319–332

    Article  Google Scholar 

  • Tarantilis PA, Tsoupras G, Polissiou M (1995) Determination of saffron (Crocus sativus L.) components in crude plant extract using high-performance liquid chromatography-UV/Visible photodiode-array detection-mass spectrometry. J Chromatogr 699:107–118

    Article  CAS  Google Scholar 

  • Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167:127–135

    Article  CAS  PubMed  Google Scholar 

  • Verma A, Moghaddam B (1996) NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 16:373–379

    CAS  PubMed  Google Scholar 

  • Xie Z, Commissaris RL (1992) Anxiolytic-like effects of the noncompetitive NMDA antagonist MK-801. Pharmacol Biochem Behav 43:471–477

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Shoyama Y, Sugiura M, Saito H (1994) Effects of Crocus Sativus L. on the ethanol-induced impairment of passive avoidance performance in mice. Biol Pharm Bull 17:217–221

    Article  CAS  PubMed  Google Scholar 

  • Zheng YQ, Liu JX, Wang JN, Xu L (2007) Effects of crocin on reperfusion induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 1138:86–94

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was co-financed by the European Union and Greek National Funds through the Research Funding Program Heracleitus II by the grant 4190.01.17 to G.G. The authors declare that the experiments comply with the current laws of Greece.

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Correspondence to Nikolaos Pitsikas.

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Georgiadou, G., Grivas, V., Tarantilis, P.A. et al. Crocins, the active constituents of Crocus Sativus L., counteracted ketamine–induced behavioural deficits in rats. Psychopharmacology 231, 717–726 (2014). https://doi.org/10.1007/s00213-013-3293-4

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  • DOI: https://doi.org/10.1007/s00213-013-3293-4

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