Grant: CIHR Fellowship

Schizophrenia is an incurable chronic and disabling mental disorder. Symptoms are classified into three domains: positive or psychotic symptoms (eg hallucinations, delusions), negative symptoms (eg anhedonia, a decreased response to rewarding stimuli), and cognitive deficits (including attentional deficits and poor decision-making). Current treatments are only effective at controlling psychosis; negative symptoms and cognitive impairments continue to affect these patients. Schizophrenia research should therefore address the entire range of symptoms to improve treatments and animal models can provide valuable information in this regard. An ideal schizophrenia model should mimic known neurochemical dysfunction present in affected patients. Schizophrenia is hypothesized to be a developmental disorder. During development, an incident may occur that permanently reduces dopamine (DA) in the prefrontal cortex. Then in late adolescence, in response to environmental stressors, DA in the striatum abnormally increases and neurons within this region become hyper-sensitive to DA. The combination of reduced DA in the prefrontal cortex and increased DA in the striatum results in the presentation of schizophrenia. The proposed experiments involve an animal model of schizophrenia based on these hypotheses. DA pathways in the prefrontal cortex will be disrupted in rats early in development, reducing DA in this region. Rats will then develop an amphetamine-induced sensitized state in late adolescence, which is dependent upon increased striatal DA. The combination of these two manipulations is analogous to the proposed pathology of schizophrenia. This two-hit model, as well as rats receiving only one treatment, will be tested on translational tasks relevant to each symptom domain. Validating the model in relation to schizophrenia-like behaviours and neurochemical abnormalities will aid in the development of ideal pharmaceutical agents by providing the ability to screen novel drugs.