Capturing the angel in "angel dust": twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans.
Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA. bita@pitt.edu
Bita
B
Moghaddam
John H
JH
Krystal
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D010054:Brief Psychiatric Rating Scale; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D009488:Neurosciences; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011605:Psychoses, Substance-Induced / Q000503:physiopathology; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D057170:Translational Research, Biomedical
D014150:Antipsychotic Agents; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine; D010622:Phencyclidine; D004298:Dopamine