This proposal is the second revision of our competing renewal of our previous R01 studying dopamine pathology in schizophrenia. Based on the results of those studies we have turned our interest to the anatomical and neurochemical basis of treatment response or resistance. The typical symptoms of schizophrenia are psychosis, cognitive impairments and negative symptoms, and the treatment available is based in the use of antipsychotic medications, which primarily act blocking dopamine receptors in some degree. Unfortunately, not all patients respond to treatment, and in those who do, only psychotic symptoms are usually improved. In fact, approximately 30% of patients do not respond to these treatments at all, and are considered treatment-non-responders or treatment resistant. This clearly points out the need of finding the basis of these differences in treatment response in order to develop new therapies. The basis of these differences are currently unknown but some lines of evidence (including work performed by our group), point towards different dopamine anomalies ('dopamine phenotypes") in treatment-responders vs treatment-non- responders (Abi-Dargham et al, 2000;Roberts et al, 2009). The overall goal of this proposal is to identify components of the dopaminergic transmission that may underlie the existence of different "dopamine phenotypes" in treatment-responders vs treatment-non- responders. We propose a multitier approach to analyze dopamine pathologies in postmortem substantia nigra-ventral tegmental area (SN/VTA), [the area of the brain that houses the majority of the dopaminergic cells], in schizophrenia treatment-responders vs treatment-non-responders, comparing also with healthy controls. We will test the capability of these dopamine neurons to produce dopamine, the health of the dopamine cell populations, and the modulation of these cells by the glutamatergic system, all with the common goal of identifying specific anomalies that can be linked to success/failure in treatment response. Even when dopamine has a central role in schizophrenia pathology, there are very scarce studies on anomalies of the SN/VTA in schizophrenia, and even rarer is the study of treatment response in postmortem human brain, both facts making our project unique. More importantly, finding neuroanatomical and neurochemical biomarkers of treatment response should allow the identification of potential targets for the development of new and more specific therapies, as well as provide a framework for the development of neuroimaging tools aimed to the prediction of treatment response outcomes.

Public Health Relevance

Identifying the neuroanatomical and neurochemical substrates underlying treatment response/resistance to the currently available antipsychotic medications in schizophrenia should provide new potential targets for treatment intervention, as well as a framework to develop tools for the prediction of treatment outcomes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
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University of Alabama Birmingham
Schools of Medicine
United States
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Rice, Matthew W; Roberts, Rosalinda C; Melendez-Ferro, Miguel et al. (2014) Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia. Brain Struct Funct :
McCollum, L A; Roberts, R C (2014) Ultrastructural localization of tyrosine hydroxylase in tree shrew nucleus accumbens core and shell. Neuroscience 271:23-34
Bolding, Mark S; Reid, Meredith A; Avsar, Kathy B et al. (2013) Magnetic transfer contrast accurately localizes substantia nigra confirmed by histology. Biol Psychiatry 73:289-94
Melendez-Ferro, Miguel; Rice, Matthew W; Roberts, Rosalinda C et al. (2013) An accurate method for the quantification of cytochrome C oxidase in tissue sections. J Neurosci Methods 214:156-62
Perez-Costas, Emma; Melendez-Ferro, Miguel; Rice, Matthew W et al. (2012) Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra. Front Psychiatry 3:31
Perez-Costas, Emma; Melendez-Ferro, Miguel; Roberts, Rosalinda C (2010) Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J Neurochem 113:287-302
Perez-Costas, Emma; Gandy, Johanna C; Melendez-Ferro, Miguel et al. (2010) Light and electron microscopy study of glycogen synthase kinase-3beta in the mouse brain. PLoS One 5:e8911
Dwivedi, Yogesh; Rizavi, Hooriyah S; Zhang, Hui et al. (2010) Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subject Biol Psychiatry 67:1017-25
Wonodi, Ikwunga; Hong, L Elliot; Stine, O Colin et al. (2009) Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B:282-9
Melendez-Ferro, Miguel; Perez-Costas, Emma; Roberts, Rosalinda C (2009) A new use for long-term frozen brain tissue: golgi impregnation. J Neurosci Methods 176:72-7

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