Page 75 - ITPS-8-2

INNOSC Theranostics and
Pharmacological Sciences Ketamine and SOD activity in schizophrenia

antioxidant enzyme activity are implicated in the working memory. In vivo microdialysis study have shown
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pathogenesis of schizophrenia. Increased SOD enzymatic that acute KET administration impairs working memory,
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activity has been reported in schizophrenic patients. In which is accompanied by increased dopamine release in
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severe schizophrenia, changes in SOD enzymatic activity the PFC. In patients with schizophrenia, KET exacerbates
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have been experimentally shown to be associated with the both positive and negative symptoms, indicating that
general pathology of the disorder and the exacerbation of NMDA receptor antagonists may act on a neural system
its symptoms. 2 already compromised in psychosis. 15
Ketamine (KET), an N-Methyl-D-Aspartate (NMDA) In animal models, KET induces behavioral and
receptor antagonist, is commonly used in preclinical electrophysiological changes that parallel psychosis-
research to model schizophrenia in animals. Its sub- like features observed in humans. Late adolescence and
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anesthetic doses have been shown to induce a variety of early adulthood stages reflect the developmental periods
schizophrenia-like symptoms, including hyperactivity, when schizophrenia symptoms typically emerge in
cognitive deficits, social withdrawal, anxiety and behavioral humans. Behavioral, biochemical, and cognitive deficits
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changes, which mimic positive, negative, and cognitive induced at this stage closely mimic human schizophrenia
symptoms of the disorder as seen in humans. Acute or phenotypes, including hyperactivity, sensorimotor gating
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repeated KET administration has been used to induce deficits, and cognitive impairments. Studies using
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schizophrenia-like phenotypes and to study the underlying pharmacological interventions, such as glutamate receptor
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neurobiological mechanisms in animal studies. The antagonists like KET, demonstrate that developmental
drug’s action on glutamatergic neurotransmission, manipulations during late adolescence or early adulthood
specifically its antagonism of NMDA receptors, leads to effectively reproduce schizophrenia-like behaviors. This
an increase in dopamine release, which is thought to be allows for the evaluation of therapeutic interventions,
the underlying mechanism of some of these effects. The such as antipsychotics or antioxidants, during critical
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antagonistic effect of KET on NMDA receptors alters neurodevelopmental windows in rodents. Repeated
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cognitive functions, as demonstrated in assessments of administrations of low doses of KET (10, 20, and
working memory using alternation tasks, which could 30 mg/kg) have been shown to increase glutamate release
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be associated with anxiety overload. In human studies, in the PFC, thus non-NMDA receptors activation triggers
administration of sub-anesthetic doses of KET in healthy dysregulation of dopaminergic neurotransmission in the
volunteers blocks NMDA receptors, thereby interfering PFC, thereby contributing to cognitive impairments.
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with sensory information processing. A single low dose Psychotic-like phenotype induction by KET suggests
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of KET in the range of 10 – 30 mg/kg induces impaired that endogenous dysfunction or dysregulation of NMDA
working memory in a dose-dependent manner; the receptor-mediated transmission may play a role in
impaired working memory can be reversed by atypical schizophrenia pathogenesis, potentially in conjunction
antipsychotic drugs such as risperidone (RISP). Behavioral with altered dopamine transmission. Furthermore,
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paradigms such as hyperactivity and space exploration in NMDA receptor antagonism affects serotonergic and
the open field test (OFT) are used to assess psychotic-like GABAergic transmission in the PFC. Most animal studies
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behaviors in rodents. The simplicity, reproducibility, and on NMDA receptor blockade focus on single-dose drug
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versatility of these paradigms make them essential tools administration to induce schizophrenia-like phenotypes
for evaluating schizophrenia-like behaviors in animal and mimic behavioral deficits. However, the effects of
models. Schizophrenia, a complex psychiatric disorder, is prolonged NMDA receptor antagonism in exploring
phenotypically characterized by hyperactivity as a positive the behavioral and neurobiological abnormalities of
symptom in rodents. The OFT is particularly effective in schizophrenia remain underexplored. 7
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evaluating hyperactivity, which is integral to schizophrenia
pathophysiology. Behavioral tests, including the elevated Chronic exposure to sub-anesthetic doses of KET
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plus maze (EPM), have been extensively used to assess alters oxidative stress markers, including changes in SOD
anxiety, risk-taking behavior, and cognitive impairments, enzymatic activity, potentially driven by the activation
which are often altered in schizophrenia. The validity of of nicotinamide adenine dinucleotide phosphate
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these tests in assessing cognitive impairments lies in their oxidase in neurons. 18,19 These changes may also reflect a
ability to evaluate excessive and chronic anxiety, which compensatory response to oxidative damage. 19,20 KET-
may be interpreted in the context of thinking, memory, induced schizophrenia models not only mimic behavioral
concentration, and decision-making. Brain cognitive symptoms but also replicate underlying biochemical
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processing is a function of dopaminergic transmission in abnormalities, such as the dysregulation of the
the prefrontal cortex (PFC) and is critically important for endogenous antioxidant system. 21,22 While SOD is critical

Volume 8 Issue 2 (2025) 69 doi: 10.36922/itps.6372