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
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
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
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
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
Bitanihirwe BK, Woo TU (2011) Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 35:878–893
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
Calev A, Venables PH, Monk AF (1983) Evidence for distinct verbal memory pathologies in severely and mildly disturbed schizophrenics. Schizophr Bull 9:247–264
Cavoy A, Delacour J (1993) Spatial but not object recognition is impaired by aging in rats. Physiol Behav 53:527–530
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
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
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
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
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
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
Field JR, Walker AG, Conn PJ (2011) Targeting glutamate synapses in schizophrenia. Trends Mol Med 17:689–698
Freedman R (2003) Schizophrenia. N Engl J Med 349:1738–1749
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
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
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
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
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
Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308
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
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
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
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
Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467
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
Moghaddam B, Adams BW (1998) Reversal of phencyclidine effcts by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352
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
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
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
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
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
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
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
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
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
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
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
Reddy RD, Yao JK (1996) Free radical pathology in schizophrenia: a review. Prostaglandins. Luk Essent Fatty Acids 55:33–43
Rios JL, Recio MC, Ginger RM, Manz S (1996) An update review of saffron and its active constituents. Phytother Res 10:189–193
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
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
Sams-Dodd F (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7:3–23
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
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
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
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
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
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
Xie Z, Commissaris RL (1992) Anxiolytic-like effects of the noncompetitive NMDA antagonist MK-801. Pharmacol Biochem Behav 43:471–477
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
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
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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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