MAR 18, 2015 06:00 AM PDT

Keynote -Dopamine System Dysregulation in the Pathophysiology of Schizophrenia and Depression

Presented At Neuroscience
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  • Distinguished Professor of Neuroscience, Professor of Psychiatry and Psychology Department of Neuroscience, University of Pittsburgh
      Dr. Anthony A. Grace is a Distinguished Professor of Neuroscience and a Professor of Psychiatry and Psychology at the University of Pittsburgh in Pittsburgh, PA.  He received his Ph.D. from Yale University School of Medicine with Dr. Benjamin S. Bunney and had postdoctoral training with Dr. Rodolfo Llinas in the Department of Physiology and Biophysics at New York University School of Medicine.  Dr. Grace has been involved in translational research related to the dopamine system for over 30 years.   His early work pioneered the mode of action of antipsychotic drugs, and the identification and characterization of dopamine-containing neurons, and was the first to provide a means to quantify their activity state and pattern in a way that is the standard in the literature.  His current work involves novel treatments for schizophrenia and its prevention, the role of dopamine in anhedonia and affective disorders, and the mode of action of ketamine and novel antidepressant drugs.  Dr. Grace has received several awards for his research, including the Paul Janssen Schizophrenia Research Award and the Lilly Basic Scientist Award from the International College of Neuropsychopharmacology, the Efron Award from the American College of Neuropsychopharmacology, as well as a NIMH MERIT award, a Distinguished Investigator award from the National Alliance for Research in Schizophrenia and Depression, the Judith Silver Memorial Investigator Award from the National Alliance for the Mentally Ill, a Fellow of the American Association for the Advancement of Science, and appointment as a Distinguished Professor of Neuroscience at the University of Pittsburgh.  He is also a past member of the governing council of the American College of Neuropsychopharmacology and is on the editorial board fornumerous leading journals in the field.
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    The dopamine-containing neurons of the midbrain have been implicated in a broad array of psychiatric disorders, ranging from schizophrenia to drug abuse and depression. However, studies seem to indicate that it is not the dopamine neurons themselves that are responsible for these pathological states, but instead the disorders appear to arise due to a disruption of dopamine neuron regulation by afferent inputs. Dopamine neurons recorded in vivo are known to exhibit multiple functional activity states, including baseline tonic firing and phasic activation in response to salient stimuli. Phasic burst firing is believed to be the behaviorally relevant “signal” of the dopamine neuron, whereas the level of tonic discharge represents the “gain” or the level of amplification of this signal. This tonic gain is differentially regulated by multiple brain regions, including the hippocampus, the amygdala, and the prefrontal cortex. Disruptions in these regions can interfere with the normal tonic/phasic balance within the dopamine system. Electrophysiological and behavioral studies in animal models of psychiatric disorders, as well as and human imaging studies in patients, suggest that this disruption may underlie the pathological state of the dopamine system that is present in psychiatric disorders. Specifically, we found that hippocampal hyperactivity in schizophrenia may be responsible for the hyperdopaminergic state of psychosis, whereas prefrontal cortical-amygdala overdrive diminishes reward-related dopamine neuron activity leading to anhedonia in depression. This type of information can contribute both to a better understanding of the pathophysiology of major psychiatric disorders, as well as glean insights into novel avenues of treatment and potentially in preventing the emergence of these disorders.

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