Schizophrenia is a severe mental disorder. The current treatments can alleviate the psychotic symptoms, while the social and cognitive deficits lack effective medication. One of the unmet needs for improving treatments is the lack of valid preclinical disease models.¹ Therefore, we conducted fMRI experiments to characterize the acute phencyclidine (PCP)-induced dose-dependent schizophrenic symptoms. The findings were confirmed with microdialysis measurements and behavioral tests.All animal procedures were approved by the National Animal Experiment Board. The effects of acute PCP (1-5 mg/kg s.c.) were investigated. Experiments were done with male Wistar and Lister hooded rats. During fMRI (7T Bruker, TR 2 s, TE 45 ms, FOV 2.5x2.5 cm2, 64x64 matrix, and 11x1.5 mm slices), rats were anesthetized with urethane (1.0 g/kg i.v.) and mechanically ventilated. Arterial blood samples were obtained to adjust the blood gases. One 2-h scan (3600 volumes) was obtained from each subject, where PCP was administered after 30min. In microdialysis experiments, the dopamine and PCP concentrations were quantified from medial prefrontal cortex (mPFC) and striatum for 5h period. In behavioral tests, the effects of PCP on locomotor activity, social interaction, and reversal learning were investigated. Locomotor activity was followed for 2 h after PCP administration. In social interaction test the behavior of two rats was followed for 10 min, preceding a housing in a single cage for 4-7 days and PCP treatment 45 min before test. In touchscreen-based two-choice visual discrimination test, the effects of PCP on reversal learning and choice accuracy were studied. All values in figures are mean±SEM.All physiologic parameters were in normal range throughout the fMRI experiments. The localization of PCP-induced blood oxygenation level dependent (BOLD) signal changes is shown in Figure 1. The spatial distribution is expanding dose-dependently up to 3 mg/kg, where maximum spatial response, yet highly region-specific, appears to be achieved. Similar observations are made in group-level time series and area-under-curve (AUC) values (Figure 2). Several of the observed regions express clear dose-dependent increasing trend in AUC values from 1 to 3 mg/kg, including several schizophrenia-related key regions, such as in mPFC, nucleus accumbens, striatum, thalamus, and hippocampus. The extracellular DA and PCP levels from striatum and mPFC are shown in Figure 3A. The BOLD time series (Figure 2) were highly correlating (R²=0.58-0.81) with corresponding extracellular mean DA and PCP time series (Figure 3B). The functional connectivity (FC) analysis revealed extensive, significant, and dose-dependent PCP-induced changes in several measures of FC (Figure 4). Multiple connections from schizophrenia-related key regions, such as from mPFC, hippocampus and thalamus, were heavily disrupted by PCP. Moreover, the connectivity of cortical regions collapsed with the higher PCP doses. The PCP-induced changes in locomotor activity are shown in Figure 5A, and the changes are highly correlating with the changes observed in FC of motor cortices (Figure 5B). The visual discrimination test shows significant impairment in reversal learning in PCP-treated rats (Figure 5C). Similarly, social interaction is decreased by PCP (Figure 5D).Clear dose-dependent PCP-induced effects in BOLD signal and FC were observed. Moreover, these changes were specifically localized to the key regions associated with schizophrenic symptoms. FMRI data indicated that high PCP doses ≥ 3 mg/kg induced strong and extensive changes in brain, which may be attributed to psychotic symptoms. With doses ≤ 2 mg/kg the changes were modest, but still visible in the key regions, such as in the parts of mesolimbic pathway and hippocampus, suggesting the presence of social and cognitive deficits. These findings were confirmed with microdialysis experiments and behavioral tests. Dopamine levels were increased in mPFC already by PCP 2 mg/kg, while in striatum by 3 mg/kg, showing that PCP has regional dose-dependent effects in the key regions. Locomotor activity was significantly increased with doses ≥ 3 mg/kg, which is a marker for psychotic symptoms. Reversal learning test shows that PCP 1.5 mg/kg impairs significantly the learning (cognitive deficit) and disturbs the social interaction (social deficit).Acute PCP administration was found to induce clear dose-dependent changes in BOLD signal and FC. The changes occurred in the key regions associated with schizophrenia. The strong effects, resembling psychotic symptoms, were achieved with doses ≥ 3 mg/kg. More modest effects, possibly social and cognitive deficits, were achieved with ≤ 2 mg/kg. The findings were confirmed with microdialysis measurements and behavioral tests. Thus, acute PCP at low doses (≤ 2 mg/kg) can be used to model specifically the social and cognitive deficits without psychotic symptoms.