Objective By establishing a schizophrenic rat model, to observe the changes in protein kinase A (PKA) and chemokine-5 (CCL5) expression in the prefrontal cortex, to clarify the mechanism of neurological injury, and to provide a reference for guiding clinical treatment. Methods The experimental rats were randomly divided into two groups: the control group (received subcutaneous injection of normal saline, n = 15) and the schizophrenia model group (received daily intraperitoneal injection of amphetamine at 0. 5 mg/ kg to establish a model of schizophrenia, n = 15). Nuclear pyknosis of the prefrontal neurons was detected by pathological observation using hematoxylin-eosin staining. The rat model of schizophrenia was verified by the Sams-Dodd stereotype behavior scoring system and open field test. The expression levels of PKA and CCL5 mRNA were detected by quantitative reverse transcription polymerase chain. The levels of PKA and CCL5 protein in experimental rats were detected by enzyme-linked immunosorbent assay. The interleukin (IL)- 1α, IL-1β, and IL-17 protein expression levels were detected by western blotting. Results The stereotypic behavior score was higher in the schizophrenia model group than control group (2. 38±0. 26 vs. 0. 85±0. 14, respectively), and the open field test score was higher in the schizophrenia model group than control group (326. 58± 15. 47 vs. 198. 55± 12. 58, respectively) ( P <0. 05). The expressions of PKA and CCL5 mRNA were higher in the schizophrenia model group than control group ( P <0. 05). The PKA and CCL5 contents were higher in the schizophrenia model group (4. 21±1. 05 and 3. 76±0. 51 mmol/ g, respectively) than in the control group (2. 46±0. 67 and 1. 35±0. 24 mmol/ g, respectively) ( P < 0. 05). The protein expressions of the pro-inflammatory factors IL-1α, IL-1β, and IL-17 were higher in the schizophrenia model group (2. 85±0. 35, 2. 15±0. 27, and 2. 16±0. 32, respectively) than control group (1. 02±0. 17, 0. 94±0. 13, and 1. 05±0. 25, respectively) ( P <0. 05). The schizophrenia model group had a higher proportion of positive cells than the control group, and the anterior frontal pyramidal cells showed more nuclear pyknosis and cytoplasmic eosinophilia. Red staining was enhanced in the schizophrenia model group ( P <0. 05). Conclusions The expressions of PKA and CCL5 in the prefrontal cortex are higher in rats with than without schizophrenia and induce cognitive impairment.