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Prepubertal chronic stress and ketamine administration to rats as a neurodevelopmental model of schizophrenia
Edward Ram1, Shani Raphaeli, Avi Avital
1Division of General Surgery, Hasharon Hospital Rabin Medical Center, Petach Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Israel.
Insights
Chronic stress and ketamine exposure in young rats mimic schizophrenia symptoms. This preclinical model reveals deficits in motor activity, anhedonia, and cognitive impairments, offering insights into the disorder.
Area of Science:
- Neuroscience
- Psychiatry
- Animal Models
Background:
- Schizophrenia vulnerability is linked to stress and early-life N-methyl-D-aspartate (NMDA) receptor dysfunction.
- NMDA receptor alterations during central nervous system development can lead to psychosis and cognitive deficits.
Purpose of the Study:
- To investigate the behavioral effects of chronic stress and ketamine administration during a critical developmental window in male rats.
- To establish a novel animal model for schizophrenia-like symptoms.
Main Methods:
- Male rats were exposed to chronic stress (postnatal days 30-60) and/or ketamine (postnatal days 41-45).
- Behavioral assessments included locomotor activity, sucrose preference test (anhedonia), object recognition, eight-arm radial maze (learning), and prepulse inhibition (PPI).
Main Results:
- Ketamine and ketamine+stress groups showed increased locomotor activity; stress-only group showed decreased activity.
- Anhedonia (decreased sucrose intake) was observed in stress and ketamine+stress groups.
- Ketamine+stress group exhibited impaired object recognition, learning, and prepulse inhibition.
Conclusions:
- Combined prepubertal chronic stress and ketamine administration create a valid animal model for schizophrenia-like symptoms.
- This model highlights the impact of early-life stress and NMDA receptor modulation on neurodevelopmental psychiatric disorders.
Abstract:
Increased vulnerability to psychiatric disorders, such as schizophrenia, has been associated with higher levels of stress. In the early development of the central nervous system, changes in function of glutamatergic N-Methyl-D-aspartate (NMDA) receptors can possibly result in the development of psychosis, cognitive impairment and emotional dysfunction in adulthood. Thus, in this study we examined the behavioural consequences of the exposure of male rats to chronic stress (postnatal days 30-60) and ketamine administration (postnatal days 41-45); both during a sensitive developmental time window. We found that the locomotor activity of both ketamine and ketamine+chronic stress groups was significantly higher compared with that of the control rats. In contrast, the locomotor activity of the chronic stress group was significantly lower compared with all other groups. Examining anhedonia in the sucrose preference test we found a significantly decreased sucrose intake in both ketamine+chronic stress and the chronic stress groups compared with the control rats. No significant differences were observed in sucrose intake between the control and the ketamine group. The object recognition test revealed that the attention to the novel object was significantly impaired in the ketamine+chronic stress group. Similarly, the ketamine+chronic stress group showed the poorest learning ability in the eight-arm radial maze, starting on the 8th day. Finally, throughout the different pre-pulse intensities, the ketamine+chronic stress group showed impaired PPI compared with all other groups. The results indicate that the combination of prepubertal onset of chronic stress and ketamine may serve as a valid novel animal model for schizophrenia-like symptoms.
