Effect of Sarcosine (a Glycine Transport 1 Inhibitor) and Risperidone (an Atypical antipsychotic Drug) on MK-801 Induced Learning and Memory Deficits in Rats

Abstract

The present study was carried out to evaluate whether the combined administration of sarcosine with risperidone possess any advantageous effects on dopaminergic and NMDA receptor-mediated glutamatergic neurotransmissions as compared to single drug administration in rats. The Wistar rats were divided into 7 groups each with different treatments. MK-801 (0.1 mg/kg, i.p.) was injected as single dose on 14^th day for inducing learning and memory deficits in animals. Sarcosine (300 and 600 mg/kg, i.p.) and risperidone (0.2 mg/kg, i.p.) were administered daily for 14 days. Spatial habituation learning and hole board tests were performed on 14^th day followed by measurement of GABA and 5-HT levels in brain tissues of rats. Pretreatment of sarcosine (600 mg/kg, i.p.) non-significantly improved learning and memory deficits induced by non-competitive NMDA receptor antagonist MK-801, significantly increased the GABA and decreased the 5-HT levels (p<0.05). Combined administration of sarcosine (300 mg/kg, i.p.) with risperidone (0.1 mg/kg, i.p.) synergistically improved cognitive deficits significantly, decreased % errors in hole board learning test, and increased centre time, corner time in spatial habituation learning test (p<0.05). The combined administration also potentiated the GABA and decreased 5-HT levels, indicating that the increased synaptic glycine concentrations may enhance NMDA receptor function which is directly linked with increased GABAergic transmission in striatum region and decreased 5-HT levels showed antagonistic action hence, enhancing the cognition. Our results suggest that combined administration of sarcosine with risperidone may strengthen glutamatergic tone in striatum. Thus, it may be a novel regime to improve psychotic symptoms and cognitive deficit in schizophrenia.

Key words

sarcosine - NMDA receptor - glyceine transport inhibitor - GABA - 5-HT

• References

• 1 Lindenmayer JP. Treatment refractory schizophrenia. Psychiat Q winter 2000; 71: 373-384
• 2 Leucht S, Barnes TRE, Kissling M et al. Relapse Prevention in Schizophrenia with New-Generation Antipsychotics: A Systematic Review and Exploratory Meta-Analysis of Randomized. Controlled Trials 2003; 160: 1209-1222
• 3 Arnt J, Skarsfeldt T, Hyttel J. Differentiation effects of classical and novel antipsychotic using animal model. Int Clin Psychopharmocol 1997; 12 (Suppl. 01) S9-S17
• 4 Yoon JK, Kim DE, Koo JS. Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer. J Transl Med 2014; 12: 149 Published online May 28, 2014
• 5 Bartolomeis AD, Sarappa C, Magara S et al. Targeting glutamate system for newer antipsychotic approaches: Relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol 2012; 682: 1-11
• 6 Chen HH, Stoker A, Markou A. The glutamatergic compound sarcoine and N-acetylcysteine ameliorate prepluse inhibition defict in metabotrophic glutamate 5 receptor knockout mice. Psychopharmacology 2010; 209: 343-350
• 7 De Lama MN, Laranja DC, Bromberg E et al. Pre- or post training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behavioural Brain Res 2005; 156: 139-143
• 8 Grayson B, Idris NF, Neill JC. Atypical antipsychotics attenuate a sub chronic PCP induced cognitive deficit in the novel object recognition task in the rat. Behavioural Brain Res 2007; 184: 31-38
• 9 Meltzer HY, Mcgurk SR. The effects of clozapine, risperidone and olanzapine on cognitive function in schizophrenia. Schizophrenia Bull 1995; 25: 233-255
• 10 Hashimoto K. Glycine Transport Inhibitors for the Treatment of Schizophrenia. Open Med Chem J 2010; 4: 10-19
• 11 Hashimoto K, Fujita Y, Ishima T et al. Phencyclidine-induced cognitive deficits in mice is improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine. Euro Neuropsychopharmacol 2008; 18: 414-421
• 12 Strzelecki D, Szyburska J, Jabłońska JR. Two grams of sarcosine in schizophrenia Is it too much? A potential role of glutamate-serotonin interaction. Neuropsychiatric Disease and Treatment 2014; 10: 263-266
• 13 Dai H, Krost M, Carey RJ. A new methodological approach to the study of habituation: The use of positive and negative behavioural indices of habituation. J Neurosci Methods 1995; 62: 169-174
• 14 Brown GR, Nemes C. The exploratory behaviour of rat in the hole- board apparatus: Is head-dipping a valid measure of neophilia?. Behaviour Process 2008; 78: 442-448
• 15 Babu CS, Kesavanarayanan KS, Kalaivani P et al. A Simple Densitometric Method for the Quantification of Inhibitory Neurotransmitter Gamma-Amino butyric Acid (GABA) in Rat Brain Tissue. Chromatography Research International Volume 2011; 2011 Article ID 732409, 5 pages http://dx.doi.org/10.4061/2011/732409
• 16 Curzon G, Green AR. Rapid method for the determination of 5- hydroxyl trytamine and 5-hydroxyindolacetic acid in small region of rat brain. Life science Oxford 1968; 7: 653-657
• 17 Harvey RJ, Benjamin KY. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nature Reviews Drug Discovery 2012; 12: 866-885
• 18 Wojciech Z, Gunter Q, Wojciech D. Infusion of (+)-MK-801 and Memantine contrasting effects on maze learning in rats with entorhinal cortex lesion. Eur J Pharmacol 1996; 296: 239-246
• 19 Nakajima M, Inui A, Miura M et al. Effects of pancreatic polypeptide family peptides on feeding and learning behaviour in mice. J Pharmacol Exp Ther 1994; 268: 1010-1014
• 20 Sutcliffe JS, Marshall KM, Neill JC. Influence of gender on working memory in the novel object recognition task in the rat. Behav Brain Res 2007; 177: 117-125
• 21 Black MD, Varty GB, Arad M et al. Procognitive and antipsychotic efficacy of Glycine transporter inhibiters (Gly-T I) in acute neurodevelopmental model of schizophrenia: Latent inhibition study in rat. Psychopharmacol (Berl) 2009; 202: 385-396
• 22 Singer P, Feldon J, Yee BK. Interactions between the glycine transporter 1 (GlyT1) inhibitor SSR504734 and psychoactive drugs in mouse motor behaviour. Eur Neuropsychopharmacol 2009; 19: 571-580
• 23 Coan EJ, Collingridge GL. Effects of phencyclidine, SKF10, 047 and related psychotomimetic agents on N-methyl-D-aspartate receptor mediated synaptic responses in rat hippocampal slices. Br J Pharmacol 1987; 91: 547-565
• 24 Alberati D, Moreau J, Lengyel J et al. Glycine reuptake inhibitor rg1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 2012; 62: 1152-1161
• 25 Javitt DC, Sershen S, Hashim A et al. Reversal of phencyclidine-induced hyperactivity by glycine and the Glycine uptake inhibitor glycyldodecylamide. Neuropsychopharmacology 1997; 17: 202-204
• 26 Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1995; 148: 1301-1308
• 27 Kleppner SR, Tobin AJ. GABA signalling: therapeutic targets for epilepsy, Parkinson disease and Huntington disease. in opinion on therapeutic targets 2001; 5: 219-239
• 28 Ginovart N, Kapur S. Role of Dopamine D₂ Receptors for Antipsychotic Activity. In Gross G, Geyer MA. (eds.) Current Antipsychotics, Handbook of Experimental Pharmacology. 2012. # Springer-Verlag; Berlin Heidelberg:
• 29 Gernot R, Bettina P, Jacques M. Glutamate receptor function in learning and memory. Behav Brain Res 2003; 140: 1-47
• 30 Lydiard RB. The role of GABA in anxiety disorder. J Clinical Psychiatry 2003; 64: 21-27