Broberg, Brian V; Madsen, Kristoffer H; Plath, Niels; Olsen, Christina K; Glenthøj, Birte Y; Paulson, Olaf B; Bjelke, Börje; Søgaard, Lise V
1 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre3 Synaptic Transmission I, H.Lundbeck A/S4 International Clinical Research, H.Lundbeck A/S5 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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 20mg/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 0.5mg/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 (25-33min post acutePCP injection), neoPCP animals showed significantly higher rCBV values compared to the Vehicle control group, suggesting an altered sensitivity towards 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 signalling might underlie the symptomatic changes seen in schizophrenia, adding to the construct and face validity of this model.
Behavioural Brain Research, 2013, Vol 250, p. 1-8
Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't