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Miniature Research Project Introduction
Schizophrenia is a major psychiatric disorder characterized by a large range of cognitive and behavioral symptoms and affects approximately 1% of the population (Stilo et. Al, 2010). Positive symptoms of the disorder such as paranoia and delusions are often the most well understood symptoms of schizophrenia. However, schizophrenia is also characterized by cognitive symptoms such disruptions in working memory, and negative symptoms, such as social avoidance (Carbon & Correll, 2014). The most popular treatment for the disorder is a dopamine D2 receptor antagonist, due to the dopamine hypothesis of schizophrenia, which states that hyperdopaminergic function in the caudate nucleus is the cause of positive symptoms in schizophrenia, while hypodopaminergic function in the frontal cortices is the cause of negative and cognitive symptoms in schizophrenia (Patel et. Al, 2014). This treatment is used to treat positive symptoms in schizophrenic patients. Approximately one third of patients do not show clinical improvements following this treatment (Stone et al., 2011), and these medications are ineffective in treating negative cognitive symptoms seen within the disorder, which can be debilitating. The underlying mechanism and key molecules that play a role in both the negative symptoms and cognitive deficits within schizophrenia are still unknown.
In a previous unpublished study by colleagues in another lab found using an amphetamine sensitization model of schizophrenia, which is able to induce a reversible clinical manifestation that resembles the symptoms of schizophrenia (Russig et. Al, 2003), that an increase in working memory, a decrease in sucrose preference and an increase in aggressive and avoidance behaviour occurred in amphetamine treated rats. The working memory results of this study defy the widely accepted result of the dopamine hypothesis in which one would expect to see a decrease in working memory. This arises the question, is the dopamine hypothesis enough to explain the negative and cognitive symptoms, or simply the positive symptoms? These results showed that every significant result found was a pre-frontal cortex (PFC) mediated behaviour. It has been shown in previous papers that schizophrenic patients show reduced activity in the dorsolateral PFC (DLPFC), during working memory tasks with activation levels correlated to performance (Weinberger et. Al, 1986). A study demonstrated that schizophrenic patients that perform normally on working memory tasks show higher activity in the DLPFC compared to controls (Callicott et. Al, 2003). Another study found a correlation between DLPFC activity and the severity of negative symptoms in schizophrenia patients (Wolkin et. Al, 1992). These findings suggest that changes in PFC activity may underlie the negative and cognitive symptoms of schizophrenia that have long been neglected.
In a past study (Guidotti et. Al, 2000), the authors observed healthy patients versus depressed, schizophrenic, bipolar disorder and psychosis patients, and saw a major deficit in the number of GAD67 proteins and mRNAs. These deficits are the most robust finding when comparing patients who experience the negative and cognitive symptoms of schizophrenia to healthy subjects. Another study (Fujihara et. Al, 2015) demonstrated that knocking out GAD67 in PV interneurons showed a deficit for PPI, which is a hallmark behavioural task that is translational for schizophrenia and saw deficits in social behavior which is also seen in the negative symptoms of schizophrenia. These findings strongly point to a role of these interneurons in the pathophysiology of schizophrenia. This brings forward an important question, could amphetamine treatment lead to behavioural modifications via changes in interneuron number? Due to the findings of past studies that suggest changes in PFC activity may underlie the negative symptoms and cognitive symptoms of schizophrenia, this research study will be asking what is the effect of Amphetamine pre-treatment on interneuron number in the prefrontal cortex? This question will address the gaps in knowledge about the underlying role of the prefrontal cortex in schizophrenia and the symptoms that have not been addressed. This question will also shed light on the role of the delicate balance of excitation and inhibition within the pathophysiology of schizophrenia.
- Callicott, J. H., Mattay, V. S., Verchinski, B. A., Marenco, S., Egan, M. F., & Weinberger, D. R. (2003). Complexity of Prefrontal Cortical Dysfunction in Schizophrenia: More Than Up or Down. American Journal of Psychiatry,160(12), 2209-2215. doi:10.1176/appi.ajp.160.12.2209
- Carbon, M., & Correll, C. U. (2014). Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues in clinical neuroscience, 16(4), 505-24.
- Fujihara, K., Miwa, H., Kakizaki, T., Kaneko, R., Mikuni, M., Tanahira, C., . . . Yanagawa, Y. (2015). Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes. Neuropsychopharmacology,40(10), 2475-2486. doi:10.1038/npp.2015.117
- Guidotti, A., Auta, J., Davis, J. M., Gerevini, V. D., Dwivedi, Y., Grayson, D. R., . . . Costa, E. (2000). Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder. Archives of General Psychiatry,57(11), 1061. doi:10.1001/archpsyc.57.11.1061
- Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P & T : a peer-reviewed journal for formulary management, 39(9), 638-45.
- Russig, H., Durrer, A., Yee, B., Murphy, C., & Feldon, J. (2003). The acquisition, retention and reversal of spatial learning in the morris water maze task following withdrawal from an escalating dosage schedule of amphetamine in wistar rats. Neuroscience,119(1), 167-179. doi:10.1016/s0306-4522(03)00045-9
- Stilo, S. A., & Murray, R. M. (2010). The epidemiology of schizophrenia: replacing dogma with knowledge. Dialogues in clinical neuroscience, 12(3), 305-15.
- Steeds, H., Carhart-Harris, R. L., & Stone, J. M. (2014). Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology,5(1), 43-58. doi:10.1177/2045125314557797
- Weinberger, D. R. (1986). Physiologic Dysfunction of Dorsolateral Prefrontal Cortex in Schizophrenia. Archives of General Psychiatry,43(2), 114. doi:10.1001/archpsyc.1986.01800020020004
- Wolkin, A. (1992). Negative Symptoms and Hypofrontality in Chronic Schizophrenia. Archives of General Psychiatry,49(12), 959. doi:10.1001/archpsyc.1992.01820120047007
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