Connecting positive and negative symptoms of schizophrenia via the NMDA and Dopaminergic processes. Abstract Phillips and Silverstein largely exclude the presence of the positive schizophrenic symptoms within their article. If it could be proven that NMDA receptor function and dopamine synapse function were connected in one continuous system, then an underlying cause for both positive and negative symptoms of schizophrenia may be identifiable. The evidence for a potential link that the affects of the drug PCP creates between the NMDA and dopamine systems may provide evidence for an underlying influence which may then affect diagnosis and treatment of schizophrenia and similar disorders. This theory expands on the NMDA receptor channel influences mentioned in the Phillips and Silverstein (2003) target article and suggests further investigation. Schizophrenia is one of the most well known mental disorders throughout the western world. Many theories have been developed over time in an attempt to identify both a cause and a cure for schizophrenia. Although these theories have aided the continued advancement of research into the disease, a definitive underlying cause of schizophrenia remains to be identified. Without knowing what the root cause of a disease is, it is very difficult to either prevent or cure it entirely. Schizophrenia is widely considered to be heterogeneous. The symptoms are varied and include positive, negative and disorganized symptoms as the three most significant categories. The target article by Phillips and Silverstein (2003) primarily considers NMDA (Nmethyl-D-aspartate) receptor hypofunction to be a causal influence on both disorganised and negative schizophrenic symptoms. The most reliable evidence to suggest the connection between hypoactive NMDA receptors and negative symptoms of schizophrenia was collected by Javitt and Zukin (1991). Their research involved the drug PCP which, when taken in doses large enough to cause PCP-psychosis, shares many symptoms with schizophrenia. However, Phillips and Silverstein largely exclude the presence of the positive schizophrenic symptoms within their article. The Dopamine Hypothesis (Delay and Deniker, 1952) suggests that the hyperactivity of Dopaminergic synapses can cause the positive symptoms of schizophrenia. While the knowledge that NMDA receptor hypofunction may influence negative symptoms, and dopaminergic synapse hyperfunction may influence positive symptoms, there is very little evidence to connect the two systems together. If it could be proven that NMDA receptor function and dopamine synapse function were connected in one continuous system, then an underlying cause for both positive and negative symptoms of schizophrenia may be identifiable. The implications of this discovery would be to encourage further research into the underlying cause of schizophrenia and eventually into a single treatment for all major schizophrenic symptoms. It would also be evidence against the heterogeneity and for the homogeneity of schizophrenia. This commentary will provide a theory that suggests a coordinated system connecting NMDA receptor function and dopaminergic synapse function, and therefore both negative and positive symptoms of schizophrenia respectively. This theory will be an extension on the NMDA receptor research within the Phillips and Silverstein article, potentially providing areas for continued future research into the underlying biological causes of schizophrenia. Future research may also apply to mental disorders with similarities to schizophrenia, such as autism. PCP- NMDA antagonist and creates D. hypoactivity in PFC Positive Symptoms Hyperactivity of dopaminergic Synapses in the Nucleus accumbens. Dopamine hypoactivity in PFC NMDA receptor hypofunction Negative Symptoms Figure1: graphic representation of the connecting positive and negative schizophrenic symptom process. The reduced activity within the voltage dependant NMDA receptor channels causes or influences the negative schizophrenic symptoms (Fig. 1). The negative symptoms can be treated using NMDA agonists or glycine agonists that increase the NMDA function and therefore prevent the receptor from becoming hypoactive. Schizophrenic patients appear to have NMDA hypofunction as do patients who have suffered from PCPpsychosis. Drugs such as PCP and Ketamine can cause negative schizophrenic symptoms as they perform as indirect or non-competitive antagonists for NMDA receptors. The positive symptoms appear to be influenced by the dopamine pathways in the brain (Fig. 1). The dopaminergic synapses within the dorsolateral prefrontal cortex usually create enough dopamine to inhibit dopamine creation within the mesolimbic pathway, or more specifically the nucleus accumbens. It appears that in schizophrenic patients of PCP-psychosis sufferers, a loss of neurons within the prefrontal cortex causes dopaminergic hypoactivity (Jentsch et al., 1999). This limit of dopamine within the prefrontal cortex reduces the inhibitory affect on dopamine production in the nucleus accumbens. The hyperactivity of the dopaminergic synapses in the nucleus accumbens creates the positive symptoms of schizophrenia. Evidence for the connection between the two systems comes from the similarities that PCP-psychosis has with schizophrenia. Treating either ketamine or PCP-psychosis with drugs such as clozapine appears to alleviate both the positive and the negative schizophrenic based symptoms (Kinon and Lieberman, 1996). This immediately suggests a possible link between the NMDA and Dopaminergic processes. Furthermore, not only does PCP treatment act as an antagonist for NMDA receptors causing negative symptoms, but it also causes dopaminergic hypoactivity in the prefrontal cortex (Fig. 1). This then causes dopaminergic hyperactivity in the nucleus accumbens, and eventually the positive symptoms of both PCP-psychosis and schizophrenia. The potential link that the affects of the drug PCP create between the NMDA and dopamine systems may provide evidence for an underlying influence governing both the positive and negative symptoms of schizophrenia. Although this theory suggests a single process and possible underlying biological influence for both positive and negative symptoms, any possible cognitive or external causes cannot be ignored. As with most complex systems it should be expected that many other influences have a potential affect on the disorder. At its least this theory is an expansion on the biological coordination in schizophrenia that is mentioned in the target article by Phillips and Silverstein (2003). More specifically it expands on the NMDA receptor hypofunction theory by suggesting possible interactions that may occur between the NMDA receptor channels and other neurological mechanisms within the brain. At its most this theory may suggest areas of further research that may provide evidence for one or more underlying influences that connect all aspects of schizophrenia. This would suggest a more homogeneic view of the disorder. The prospects for both drug and cognitive treatment for schizophrenia may also be improved by further investigation into this theory. Identification of an underlying cause would also impact on the diagnosis and treatment of other similar disorders. Bibliography M. Colman, (2003). Oxford Dictionary of Psychology. Oxford University Press. M. S. Gazzaniga, R. B. Ivry, G. R. Mangun, (2002). 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