Abstract
Subchronic treatment with the N-methyl-d-aspartate (NMDA) antagonist phencyclidine (PCP) produces behavioral abnormalities in rodents which are considered a reliable pharmacological model of neurocognitive deficits in schizophrenia. Alterations in prefrontal neuronal firing after acute PCP administration have been observed, however enduring changes in prefrontal activity after subchronic PCP treatment have not been studied. To address this we have recorded cortical oscillations and unit responses in putative cortical pyramidal cells in subchronic PCP-treated rats (2mg/kg twice daily for 7days) under urethane anesthesia. We found that this regimen reduced theta oscillations in the medial prefrontal cortex. It further produced abnormal cortical synchronization in putative cortical pyramidal cells. These alterations in prefrontal cortex functioning may contribute to cognitive deficits seen in subchronic NMDA antagonist pre-treated animals in prefrontal-dependent tasks.
Highlights
Subchronic treatment with the non-competitive N-methylD-aspartate (NMDA) receptor antagonist phencyclidine (PCP) in rodents is used to model cognitive deficits in schizophrenia
Spectral analysis of local field potential (LFP) activity from medial prefrontal cortex (mPFC) of vehicle- or PCP-treated rats showed that the predominant activity in both groups was gathered in the lower frequency ranges (Fig. 1A)
Subchronic PCP treatment in rodents produces a number of behavioral abnormalities which model cognitive and negative symptoms of schizophrenia
Summary
Subchronic treatment with the non-competitive N-methylD-aspartate (NMDA) receptor antagonist phencyclidine (PCP) in rodents is used to model cognitive deficits in schizophrenia. Acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks (Dawson et al, 2014a) This maps onto findings that positive symptomatology in human patients is associated with prefrontal hyperactivity (Shergill et al, 2000). Repeated subchronic PCP exposure produces long-lasting behavioral deficits, which far outlast the period of drug infusion (Neill et al, 2010). It results in sustained NMDA receptor hypoactivity and disruptions in prefrontal metabolism, reduced expression of the GABA marker parvalbumin, and compromised functional integration between distributed neural systems assessed with cerebral glucose utilization (Dawson et al, 2014b). We found that subchronic PCP disrupted low-frequency oscillations in mPFC and resulted in abnormal cortical synchrony in this structure
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