Research reportA schizophrenia rat model induced by early postnatal phencyclidine treatment and characterized by Magnetic Resonance Imaging

- Early postnatal phencyclidine (neoPCP) dosing is evaluated as an animal model of schizophrenia.
- Adult animals are tested using relative cerebral blood volume, a proxy measure of brain activity.
- Acute PCP injection produce higher brain activity in neoPCP compared to vehicle control animals.
- The altered sensitivity to NMDAR blockade observed in neoPCP animals further validates the model.
- The observed changes in the medial prefrontal cortex are interesting in relation to cognition.

Better animal models are needed to aid the development of new medications to alleviate the cognitive deficits associated with schizophrenia. Growing evidence suggests neurodevelopmental insults and disturbances in NMDA receptor (NMDAR) signaling to be involved in the schizophrenia etiology. Acute administration of phencyclidine (PCP) induces schizophrenia-like symptoms in healthy volunteers and exacerbates symptoms in patients with schizophrenia. In this study, pharmacological Magnetic Resonance Imaging (phMRI) was used to evaluate if rats treated with 20 mg/kg PCP on postnatal days 7, 9, and 11 (neoPCP), compared to saline (neoVeh), were hypersensitive to acute PCP administration in adulthood (acutePCP). Intravenous administration of 0.5 mg/kg acutePCP produced robust and sustained relative cerebral blood volume (rCBV) increase in discrete frontal, neocortical, hippocampal, thalamic, and limbic brain structures in both neoPCP:acutePCP and neoVeh:acutePCP rats compared to acute saline treatment (Vehicle control group). AcutePCP injection significantly increased the rCBV response in the medial prefrontal cortex and nucleus accumbens compared to the Vehicle control group, without distinguishing neoPCP and neoVeh animals. However, at late time points (25-33 min post acutePCP injection), neoPCP animals showed significantly higher rCBV values compared to the Vehicle control group, suggesting an altered sensitivity toward NMDAR blockade in adult rats subjected to this neurodevelopmental procedure. In combination with the observed cognitive deficits revealed in this animal model, the present findings indicate that altered NMDAR signaling might underlie the symptomatic changes seen in schizophrenia, adding to the construct and face validity of this model.