# Psychosis: The Utility of Ketamine as a Pharmacological Model of Psychotic-like Symptoms in Rodents: A Review of Dosage Regimens

## TL;DR

This paper reviews how ketamine can be used in rodents to model psychosis-like symptoms, comparing different dosing methods and their effects on behavior and brain function.

## Contribution

The paper provides a comprehensive comparison of ketamine dosing regimens in rodent models to guide research on psychosis-like symptoms and treatment development.

## Key findings

- Single ketamine doses cause short-term overactivity and attention deficits but rarely long-term memory or mood changes.
- Repeated ketamine dosing, especially with recovery periods, consistently produces enduring cognitive and anxiety-like deficits resembling psychosis.
- Intravenous or intraperitoneal ketamine administration yields more reliable psychosis-like phenotypes for long-term studies.

## Abstract

Psychotic illnesses such as schizophrenia and bipolar disorder can cause hallucinations, loss of motivation, and serious problems with attention and memory, yet their brain basis is difficult to study directly in people. Researchers therefore use ketamine, an anesthetic and pain medication that, at lower doses, disrupts a major brain signaling system, to produce temporary psychosis-like changes in rodents and to test potential treatments. In this review, we compared published rodent studies that used different ketamine dosing schedules and summarized their impact on behavior test results and measurements of brain chemistry and activity. Across studies, a single ketamine dose reliably caused short-lived overactivity and often reduced attention, but it rarely produced lasting memory or mood changes. In contrast, repeated dosing, especially when followed by a drug-free recovery period, more consistently produced enduring deficits in working and long-term memory, attention, and anxiety- or depression-like behaviors, along with brain changes that resemble those reported in psychotic disorders. Overall, our synthesis provides practical guidance for selecting ketamine regimens matched to specific research goals, helping accelerate the development of effective treatments that reduce disability and the societal burden of psychotic illness.

Ketamine (KET) administration protocols vary widely in their design, with acute, sub-chronic, and chronic dosing regimens used to induce psychotic-like behavior in rodent models. This review compares representative classic and contemporary studies employing differing KET administration protocols to model psychosis in laboratory rodents. Specifically, we have focused on the behavioral tasks and analytical methods used to validate KET-induced symptoms of psychosis-like and schizophrenia-like behaviors. While variability in behavioral tasks complicates direct comparisons across studies, these findings provide a framework for selecting dosing strategies aligned with specific research objectives. Acute KET protocols are particularly suited for addiction research or as a preliminary approach preceding longer-term studies. In contrast, protocols utilizing repeated or sub-chronic, or chronic administration of KET tend to yield more comprehensive models of psychosis-like behavior and are better suited for examining the associated enduring cognitive and neurobiological impairments. Administering KET intravenously or intraperitoneally at frequent intervals or with a bolus dose, may sustain higher levels of bioavailable KET, thereby producing a more robust and reliable psychosis-like phenotype, especially relevant for investigations of long-term cognitive and neurological dysfunction.