Psychosis Pathways Converge via D2 High Dopamine Receptors PHILIP SEEMAN, 1,2 * JOHANNES SCHWARZ, 3 JIANG-FAN CHEN, 4 HENRY SZECHTMAN, 5 MELISSA PERREAULT, 5 G. STANLEY MCKNIGHT, 6 JOHN C. RODER, 7 RE ´ MI QUIRION, 8 PATRICIA BOKSA, 8 LALIT K. SRIVASTAVA, 8 KAZUHIKO YANAI, 9 DAVID WEINSHENKER, 10 AND TOMIKI SUMIYOSHI 11 1 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 2 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5S 1A8 3 Department of Neurology, University of Leipzig, Leipzig 04103, Germany 4 Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118 5 Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 6 Department of Pharmacology, University of Washington, Seattle, Washington 98195 7 Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 8 Douglas Hospital Research Center, Verdun, Quebec, Canada H4H 1R3 9 Department of Pharmacology, Tohoku University School of Medicine, Sendai 980-8575, Japan 10 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322 11 Department of Neuropsychiatry, Toyama University School of Medicine, Toyama 930-0194, Japan KEY WORDS schizophrenia; psychosis biomarker; degenerative brain; ampheta- mine; phencyclidine; gene mutations; dopamine receptors; psychosis; D2 High receptors; dopamine supersensitivity; gene knockouts ABSTRACT The objective of this review is to identify a target or biomarker of al- tered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippocampal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitiv- ity and increase the high-affinity states of dopamine D2 receptors, or D2 High , by 200– 400% in striata. Similar supersensitivity and D2 High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as re- serpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2 High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2 High states; such genes include dopamine-b-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 recep- tor, regulator of G protein signaling RGS9, and the RIIb form of cAMP-dependent pro- tein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2 High states; these include mice with knockouts of adenosine A 2A receptors, glycogen synthase kinase GSK3b, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or a D1 antagonist. The evidence suggests that there are multiple pathways that converge to elevate the D2 High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a com- Contract grant sponsor: NIMH; Contract grant number: MH-067497 to D. Grandy; Contract grant sponsors: Essel Foundation; Constance E. Lieber and Stephen Lieber, the Ontario Mental Health Foundation; NARSAD (the National Alliance for Research on Schizophrenia and Depression); the CIHR (Canadian Institutes of Health Research); NIDA (the National Institute on Drug Abuse); the SMRI (Stanley Medical Research Institute); the Dr. Karolina Jus estate; the Medland family; the O’Rorke family; Mrs. Shirley Warner; and the Rockert family. *Correspondence to: Philip Seeman, Departments of Pharmacology and Psy- chiatry, Medical Science Building, Rm. 4344, 1 King’s College Circle, University of Toronto, Toronto, Canada M5S 1A8. E-mail: philip.seeman@utoronto.ca Received 19 April 2006; Accepted 4 May 2006 DOI 10.1002/syn.20303 Published online in Wiley InterScience (www.interscience.wiley.com). V V C 2006 WILEY-LISS, INC. SYNAPSE 60:319–346 (2006)