Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized (1)H MRS study

Abstract

Acute phencyclidine (PCP) administration mimics some aspects of schizophrenia in rats, such as behavioral alterations, increased dopaminergic activity and prefrontal cortex dysfunction. In this study, we used single-voxel (1)H-MRS to investigate neurochemical changes in rat prefrontal cortex in vivo before and after an acute injection of PCP. A short-echo time sequence (STEAM) was used to acquire spectra in a 32-microL voxel positioned in the prefrontal cortex area of 12 rats anesthetized with isoflurane. Data were acquired for 30 min before and for 140 min after a bolus of PCP (10 mg/kg, n = 6) or saline (n = 6). Metabolites were quantified with the LCModel. Time courses for 14 metabolites were obtained with a temporal resolution of 10 min. The glutamine/glutamate ratio was significantly increased after PCP injection (p < 0.0001, pre- vs. post-injection), while the total concentration of these two metabolites remained constant. Glucose was transiently increased (+70%) while lactate decreased after the injection (both p < 0.0001). Lactate, but not glucose and glutamine, returned to baseline levels after 140 min. These results show that an acute injection of PCP leads to changes in glutamate and glutamine concentrations, similar to what has been observed in schizophrenic patients, and after ketamine administration in humans. MRS studies of this pharmacological rat model may be useful for assessing the effects of potential anti-psychotic drugs in vivo.

Figure 1

(a) Sagittal view of the rat brain. The box delineates the area in which spectra were acquired (32 μL). (b, c) Typical in vivo ¹H NMR spectra acquired in the prefrontal cortex area 40 min after an injection of saline (b) or PCP (c). Each spectrum corresponds to an acquisition of 128 single scans. A different line broadening was applied to each spectrum to obtain comparable linewidth for the NAA peak between spectra. Lactate (at 1.32 ppm) was strongly reduced in the animal receiving PCP (c). tCr, creatine + phosphocreatine; Glx, glutamate + glutamine; Glu, glutamate; Gln, glutamine; NAA, N-acetylaspartate; GABA, γ-aminobutyric acid; PE, phosphorylethanolamine; myoIns, myo-inositol; Lac, lactate. Please note that glucose resonances overlap with myoIns and PE peaks and are therefore not directly observable.

Figure 2

(a) Time course of the total concentration of glutamine + glutamate. The arrow indicates the time of PCP injection. Glutamine + glutamate concentration (saline, n = 6, PCP, n = 6; mean±SEM) is shown in μmol/g wet weight of tissue over time (min). (b) Percentage difference in the concentration of glutamine and glutamate between before (PRE) and after (POST) the injection of PCP (saline, (1±2)%; PCP, (1±5)%; mean±SD). (c) Time course for the ratio glutamine/glutamate (mean±SEM). The ratio was significantly higher after the injection in the PCP group (least square mean = 0.05, t = 7.83, p < 0.0001, PRE- vs. POST-PCP). (d) Percentage change in the ratio glutamine/glutamate in saline-treated (-3±5%) and PCP (±17±7%) rats, *p = 0.00016. (e) Time course for the concentration of glutamine. Glutamine concentration is shown in μmol/g wet (mean±SEM) over time (min). Glutamine concentration increased significantly after PCP injection (least square mean 0.05, t 7.83, p < 0.0001, PRE- vs. POST-PCP). (f) Percentage difference in the concentration of glutamine between before (PRE) and after (POST) the injection (saline, (-3±3)%; PCP, (12±7)%; mean±SD, *p = 0.034). (g) Time course for the concentration of glutamate. Glutamate concentration (in μmol/g wet weight, mean±SEM) decreased significantly after PCP injection (least square mean = -0.49, t = 5.06, p < 0.0001, PRE- vs. POST-PCP). (h) Percentage difference in the concentration of glutamine between before (PRE) and after (POST) the injection (saline, (1±2)%; PCP, (-5±5)%; mean±SD, *p=0.034). For (a), (c), (e), and (g), open squares are saline-treated (control) animals (n = 6); closed squares, PCP animals (n = 6). For (b), (d), (f), and (h), open bars are control animals and closed bars are PCP animals

Figure 3

(a) Time course of glucose concentration. Glucose was significantly increased immediately after the injection until 30 min (least square mean = 1.00, t = 7.06, p < 0.0001, PRE- vs. POST-PCP). (b) Percentage change in the concentration of glucose between before (PRE) and after (POST) the injection of saline (control) and PCP in rats (*p = 0.0055). (c) Time course for lactate concentration. Lactate concentration was stable after the injection of saline, but it dropped significantly after the injection of PCP (mean = 0.05, t = 7.83, p < 0.0001, PRE- vs. POST-PCP). (d) Change in lactate concentration between PRE and POST injection in control and PCP rats (*p = 0.00022, PCP vs. control). For (a) and (c), open squares are control animals (n=6); closed squares, PCP animals (n=6). For (b) and (d), open bars are saline-treated (control) animals, closed bars are PCP-treated animals. In (a) and (c), the arrow indicates the moment of injection. Glucose and lactate concentrations are reported in μmol/g wet weight of tissue over time (min). All data are mean±SEM with n=6 in both the control and PCP groups.