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The supersensitivity to dopamine that is characteristic of schizophrenia can be caused by mutations to a wide variety of genes, rather than alterations to just two or three specific genes, says a University of Toronto researcher.
In research published in the Feb. 15 edition of the Proceedings of the National Academy of Sciences, University of Toronto pharmacology professor Philip Seeman and his 16 colleagues in eight universities show that mutations to genes that have no relation to the brain's dopamine receptors can still cause those receptors to become highly sensitive to their own dopamine, a condition that leads to psychosis. By examining brain tissue from mice with various gene mutations, the researchers determined that the brain appears to compensate for the altered gene by becoming supersensitive to dopamine. Dopamine is a neurotransmitter that allows people to move, think and feel. "The altered genes may provoke the brain to respond and compensate, and compensation often involves the dopamine system going into high gear," says Seeman. "The brain knows about mistakes, and to protect itself, it makes sense for the compensation to re-adjust the dopamine system to preserve the functions - such as movement and thought - that the body and brain needs." An excessively active dopamine system can trigger the hallucinations and delusions experienced in schizophrenia, amphetamine drug abuse or Alzheimer's disease. In drug abuse, the reaction is temporary; in schizophrenia, it recurs. "This research brings together two worlds: the psychosis of drug abuse and schizophrenia," says Seeman. "There's a common denominator based on the dopamine receptor." It also offers a new direction for research into schizophrenia. "Vast amounts of money are being spent to look for the magical two or three genes that cause psychosis but it could be many genes - and that includes genes that have nothing to do with dopamine," said Seeman. "It was a real eye-opener to have all these different pathways factored in." The next step, says Seeman, is to identify and explain the mechanism that causes the brain to become supersensitive to dopamine, regardless of whether it's caused by a gene mutation or by drug use. The research was funded by the Ontario Mental Health Foundation, the National Alliance for Research on Schizophrenia and Depression, the Canadian Institutes of Health Research, the National Institute on Drug Abuse, the Canadian Psychiatric Research Foundation, the National Institute of Mental Health and the Dr. Karolina Jus estate. The other universities involved in the study were McGill University, McMaster University, Emory University, Oregon Health and Science University, Duke University, University of Kuopio (Finland) and University of Washington. Contact: Philip Seeman, Department of Pharmacology, (416) 978-4891; e-mail: philip.seeman@utoronto.ca (C) 2005 - University of Toronto Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T.
Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis.
Proc Natl Acad Sci U S A. 2005 Feb 16;
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