Ketamine-Induced Behavioral Models in Schizophrenia

Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, reliably induces transient psychotomimetic effects in humans and schizophrenia-like behaviours in animals. In rodents, sub-anaesthetic ketamine provokes hyperlocomotion, stereotyped movements and social withdrawal, modelling positive symptoms, while impairing cognitive performance and evoking behavioural despair to capture negative and cognitive dimensions. At molecular and circuit levels, NMDA receptor hypofunction triggers excessive glutamate release, dysregulated calcium signalling and oxidative stress, leading to synaptic plasticity deficits and altered neurotrophic support, notably reduced brain-derived neurotrophic factor (BDNF). These models have global significance for dissecting pathophysiological mechanisms, validating therapeutic targets and screening novel interventions, from repurposed drugs to nano-formulations. By recapitulating core features of schizophrenia across behavioural, electrophysiological and biochemical domains, ketamine-based paradigms continue to inform the development of more effective and tolerable treatments.

Research from Nature Portfolio

Intranasal administration of anthocyanin-rich blackberry extract encapsulated in chitosan nanoparticles ameliorates ketamine-induced schizophrenia-like behaviours in rats. The nano-formulation enhanced delivery to the brain, corrected positive, negative and cognitive deficits, and mitigated side effects associated with clozapine co-treatment, including metabolic disturbances and agranulocytosis. Mechanistically, the treatment restored antioxidant enzyme activity, reduced neuroinflammation by lowering tumour necrosis factor-α, and increased BDNF levels in prefrontal and hippocampal regions. This work highlights the promise of natural products combined with advanced drug-delivery systems for integrated management of schizophrenia symptoms.

Ketamine-Induced Behavioral Models in Schizophrenia publication trend

The graph below shows the total number of articles in ketamine-induced behavioral models in schizophrenia across all publications each year (not limited to Nature Index journals).

Technical terms

NMDA receptor hypofunction: Reduced activity of N-methyl-D-aspartate glutamate receptors, leading to excitatory/inhibitory imbalance and psychotomimetic effects.

Synaptic plasticity: The ability of synapses to strengthen or weaken over time, fundamental to learning and memory and disrupted in schizophrenia models.

Prepulse inhibition: A measure of sensorimotor gating in which a weak pre-stimulus reduces the reaction to a subsequent strong pulse; often impaired after ketamine.

Chitosan nanoparticles: Biocompatible polymeric carriers used to improve nasal or systemic delivery of therapeutic agents to the brain.

Behavioural despair tests: Paradigms such as forced swim and tail suspension that assess negative symptom–like immobility in rodents.

References

1. Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine. CNS Neuroscience & Therapeutics (2024).
2. Pharmacological screening of silibinin for antischizophrenic activity along with its acute toxicity evaluation in experimental animals. Frontiers in Pharmacology (2023).
3. Intranasal delivery of blackberry-loaded Chitosan nanoparticles for antipsychotic potential in Ketamine-induced schizophrenia in rats. Scientific Reports (2025).
4. Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia. JAMA Network Open (2020).
5. Oxidative Stress in the Developing Rat Brain due to Production of Reactive Oxygen and Nitrogen Species. Oxidative Medicine and Cellular Longevity (2016).
6. Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction. Frontiers in Cellular Neuroscience (2017).
7. Regional brain dysregulation of Ca2+-handling systems in ketamine-induced rat model of experimental psychosis. Cell and Tissue Research (2015).