Evaluating neurochemical changes and associated locomotor activity in a double hit schizophrenia model

Our double hit model is more robust in inducing behavioural and molecular changes involved in the negative and cognitive symptoms of schizophrenia when compared to each single hit model. Disrupted dopamine, glutamate, GABA, and cholinergic functions are implicated in the pathophysiology of positive symptoms of schizophrenia. In this study, we investigated behavioural and neurochemical changes associated with locomotor activity in schizophrenia using the double-hit model of schizophrenia. On postnatal day (PND) 23, rats were grouped (n = 8) as follows: group-housed + saline (GH), group-housed + ketamine (GHK), socially isolated + saline (SI), and socially isolated + ketamine (SIK). On PND 28, a single ketamine dose (16 mg/kg) was administered three times a week for four weeks. Thereafter, the animals were injected twice a week for the duration of the study. Isolated animals were housed singly throughout the study. On PND 86, the open field test was conducted to assess locomotor activity. On PND 88, the study was terminated, and the striatum was harvested for the measurement of the concentration of dopamine, glutamate, GABA, and acetylcholine and dopamine D2 mRNA expression. The SIK group showed more hyperactivity than the other groups (GH vs SIK, p < 0.0001; GHK vs SIK, p < 0.0001; SI vs SIK, p = 0.0003). This was accompanied by the overexpression of dopamine D2 mRNA (GH vs SIK, p < 0.0001; GHK vs SIK, p < 0.0001; SI vs SIK, p = 0.0281), with increased acetylcholine concentration (GH vs SIK, p < 0.0001; GHK vs SIK, p = 0.0004; SI vs SIK, p < 0.0001), and a decreased glutamate concentration (GH vs SIK, p < 0.0001; GHK vs SIK, p = 0.0001; SI vs SIK, p < 0.0001) and GABA concentration (GH vs SIK, p < 0.0001; GHK vs SIK, p = 0.0006; SI vs SIK, p = 0.0001). Taken together, these changes suggest that the SIK group highly represent the positive symptoms observed in schizophrenia patients. Our double hit model was able to induce neurotransmitter changes like those observed in positive symptoms of schizophrenia patients.