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Sarcosine (glycine transporter inhibitor) attenuates behavioural and biochemical changes induced by ketamine, in the rat model of schizophrenia

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Abstract

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms’ domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms’ domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.

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Data availability

The authors confirm that the data supporting the project's findings are included in the publication and its supplemental materials and that the corresponding author can provide the raw data upon reasonable request.

Abbreviations

CA:

Cornu ammonis

DA:

Dopamine

DI:

Discrimination index

DMSO:

Dimethyl sulfoxide

GlyT-1:

Glycine transporter inhibitor

GlyTIs:

Glycine transporter inhibitors

GSH:

Reduced glutathione

ip:

Intraperitoneally

IL-6:

Interleukin-6

Ket:

Ketamine

MDA:

Malondialdehyde

MTT:

Methylthiazolyldiphenyl-tetrazolium bromide

NADH:

Nicotinamide adenine dinucleotide

NMDA:

N-methyl-d-aspartate

NORT:

Novel object recognition test

OFT:

Open field test

RI:

Recognition index

Risp:

Risperidone

Sar:

Sarcosine

SOD:

Superoxide dismutase

SPT:

Sucrose preference

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Acknowledgements

The authors are grateful to the All India Council for Technical Education, New Delhi, for support.

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  1. Amit Kumar

    Present address: Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR- Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India

Authors and Affiliations

  1. Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC-CAS, Panjab University, Chandigarh (UT), 160014, India

    Amit Kumar, Ansab Akhtar, Anurag Kuhad & Sangeeta Pilkhwal Sah

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Amit Kumar

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Kumar, A., Akhtar, A., Kuhad, A. et al. Sarcosine (glycine transporter inhibitor) attenuates behavioural and biochemical changes induced by ketamine, in the rat model of schizophrenia. Exp Brain Res 241, 451–467 (2023). https://doi.org/10.1007/s00221-022-06530-4

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