Abstract
Rationale
There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated.
Objective
The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia.
Methods
Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study.
Results
Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits.
Conclusion
The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model.
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Data availability
The data obtained in all six studies we carried out in the PCP-SI model (Porsolt studies ERI17.0139, ERI18.0001, ERI18.0113, ERI18.0127, ERI18.0227, and ERI19.0098) are available from the corresponding author upon reasonable request.
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Acknowledgments
We thank David PUSHETT for reading the manuscript and providing helpful comments.
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The work was fully supported by Porsolt SAS.
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AM Hamieh and V Castagne conceived the study; AM Hamieh and AM Hernier designed the experiments; AM Hamieh, D Babin, E Sablé, and AM Hernier performed experiments; AM Hamieh analyzed the data; AM Hamieh wrote the manuscript; and V Castagne and AM Hernier reviewed the manuscript.
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Highlights
Rats administered with phencyclidine at neonatal age and socially isolated post-weaning (PCP-SI model) display locomotor hyperactivity and deficits in social recognition, prepulse inhibition, and reversal learning.
Chronic treatment with clozapine attenuates locomotor hyperactivity and social recognition deficits.
The PCP-SI model could be a useful model to evaluate potential effects of new therapeutic agents on reversing positive symptoms and cognitive/social deficits related to schizophrenia.
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Hamieh, A.M., Babin, D., Sablé, E. et al. Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits. Psychopharmacology 238, 517–528 (2021). https://doi.org/10.1007/s00213-020-05700-y
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DOI: https://doi.org/10.1007/s00213-020-05700-y