Ketamine and olanzapine alter behaviour and prefrontal-cortex BDNF differentially in male and female rats
Kalin Manooki, Mahdieh Gholami, Maryam Eslami, Salar Vaseghi, Batool Ghorbani Yekta
Scientific Reports August 23, 2025 DOI: 10.1038/s41598-025-15499-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experiment Peer reviewed |
|---|---|
| Population | Male and female rats |
| Interventions | Ketamine hydrochloride Olanzapine |
| Dose | 30 mg/kg ketamine, 6 mg/kg olanzapine |
| Duration | 5 consecutive days of ketamine administration, with olanzapine given immediately after the final ketamine dose |
| Topics | Ketamine Esketamine |
| Keywords | Olanzapine Prefrontal cortex Schizophrenia object-oriented programming Endocrinology Anesthesia Cognition |
| Citations | 3 |
| Key findings | Ketamine induced a schizophrenia-like phenotype with more pronounced effects in female rats, and olanzapine reversed many of the behavioral deficits without affecting BDNF levels in the prefrontal cortex. |
Abstract
Schizophrenia is a severe chronic neuropsychiatric disorder with a wide-range of cognitive and mental deficits and different categories of symptoms including positive, negative, and cognitive symptoms. In rodents, sub-chronic ketamine administration is a common method to induce a schizophrenia-like state. Olanzapine, an atypical antipsychotic medication, is used for the treatment and management of schizophrenia symptoms. Here, we aimed to assess the effects of ketamine, olanzapine, and their combination on cognitive and behavioral functions, as well as on brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex of male and female rats. Ketamine hydrochloride (30 mg/kg, i.p.) was administered for 5 consecutive days to induce schizophrenia-like alterations, and olanzapine (6 mg/kg, i.p.) was administered immediately after the final ketamine dose. Behavioral tests for locomotion, anxiety-like behavior, nociception, compulsive-like behavior, depression-like behavior, and memory were conducted, and BDNF mRNA levels in the prefrontal cortex were measured by quantitative real-time PCR. The results showed that ketamine increased locomotor activity and climbing behavior, decreased rearing (exploration), impaired novel object recognition memory, and lowered BDNF levels in the prefrontal cortex in both sexes. Certain effects of ketamine were sex-specific: ketamine reduced pain threshold (indicating hyperalgesia) and decreased immobility in the forced swim test (suggesting an anti-depressant-like effect) only in females. Olanzapine co-treatment restored locomotor activity and climbing and attenuated memory impairment in both sexes. Olanzapine also increased rearing and normalized pain threshold and immobility in females, indicating a mitigation of ketamine's female-specific effects. Olanzapine had no significant effect on BDNF levels. In conclusion, ketamine induced a schizophrenia-like phenotype with more pronounced effects in female rats, and olanzapine treatment reversed many of the ketamine-induced behavioral deficits in both sexes. Notably, the therapeutic actions of olanzapine in this model appear to be independent of BDNF upregulation in the prefrontal cortex.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 2
- Investigating the effects of chlorogenic acid on novel object recognition memory impairment, hyperlocomotion, and prefrontal BDNF expression in a sub-chronic ketamine-induced schizophrenia-like rat model IBRO Neuroscience Reports July 24, 2026
- Psychosis: The Utility of Ketamine as a Pharmacological Model of Psychotic-like Symptoms in Rodents: A Review of Dosage Regimens Biology January 25, 2026
Cites 5
- Psilocybe cubensis extract potently prevents fear memory recall and freezing behavior in short- but not long-term in a rat model of posttraumatic stress disorder. Behavioral Neuroscience January 18, 2024
- Effects of the Recurrent and Different Doses of Ketamine Exposure on Anxiety-like Behaviors and Locomotor Activity in Juvenile Rats Current Alzheimer Research December 1, 2022
- The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits. Pharmacology, Biochemistry, and Behavior November 1, 2022
- Sex-related differences in intravenous ketamine effects on dissociative stereotypy and antinociception in male and female rats. Pharmacology, Biochemistry, and Behavior September 22, 2020
- Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction Frontiers in Cellular Neuroscience June 28, 2017