Doctor of Philosophy (PhD)
School of Health Sciences - Faculty of Health & Behavioural Sciences
Newell, Kelly, Neurotransmitter receptor binding in the posterior cingulate cortex in schizophrenia and in the phencyclidine mouse model: an exploration of the NMDA hypofunction hypothesis of schizophrenia, PhD thesis, School of Health Sciences, University of Wollongong, 2007. http://ro.uow.edu.au/theses/610
Schizophrenia is a severe psychiatric disorder with no clear cause. Recent evidence suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction may underlie the pathogenesis of schizophrenia. The posterior cingulate cortex (PCC) has been shown to be the most susceptible brain region to damage caused by NMDA hypofunction in rodents. This suggests that the PCC may play an important role in schizophrenia pathology. However, studies examining neurotransmitter balance in the PCC in schizophrenia have until now been neglected. Furthermore, the long-term consequences of NMDA hypofunction on neurotransmitter balance in animal models have not been studied. The aims of this study were to investigate neurotransmitter receptor binding profiles in the PCC in schizophrenia, while also examining the effects of chronic phencyclidine (PCP; an NMDA antagonist) treatment on neurotransmitter receptor binding in mouse brain in the long-term following treatment. To achieve these aims, the study was divided into two parts. In experimental part A, PCC sections from 10 schizophrenia and 11 control subjects matched for age, gender and post-mortem interval were obtained from the Tissue Resource Center, Sydney. Using quantitative autoradiography, the density of several neurotransmitter receptors was examined. The results demonstrated specific alterations in neurotransmitter receptors in the PCC in schizophrenia. Specifically, increased NMDA, gamma-aminobutyric acid A (GABAA) and cannabinoid 1 (CB1) receptor density was found in this region, along with reduced muscarinic 1/4 (M1/4) and serotonin 2A (5-hydroxy-tryptamine, 5HT2A) receptor density. No changes were found in �-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate or M2/4 receptor density in the PCC in schizophrenia subjects compared to controls. These Kelly Newell Page 9 2007 results have shown for the first time that there are specific neurotransmitter imbalances in this region, and it is possible that these changes stem from NMDA hypofunction. In experimental part B, mice were treated chronically (14 days) with PCP. Using quantitative autoradiography the density of several receptors was examined in the short (1hr and 24hr) and long-term (14 days) following chronic PCP treatment. In addition, clozapine and haloperidol were tested for their ability to prevent the PCP-induced alterations in neurotransmitter receptor density. The results showed opposing effects of PCP treatment on neurotransmitter receptor density in the short compared to the longterm. While there were limited increases in NMDA receptor density in the short-term, there were widespread reductions in NMDA receptor density in the long-term following chronic PCP treatment. Muscarinic M1/4 receptor binding, which was increased in the short-term, showed reductions in the long-term in the limbic system, caudate-putamen and cortex, but not in the thalamus in which no change was found. Clozapine and haloperidol treatments were both unable to prevent the PCP-induced long-term changes in receptor density. In conclusion, this study has provided new information regarding neurotransmitter alterations in the PCC in schizophrenia and in mouse brain in the longterm following chronic PCP treatment. These findings may assist not only in understanding the pathology of schizophrenia, but also for designing new pharmacological treatments for this disease.
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