title: The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.
abstract: The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.
authors.affiliation: Psychosis Studies, King's College London, London, United Kingdom; MRC Clinical Sciences Centre, Imperial College Hammersmith Hospital, London, United Kingdom. Electronic address: oliver.howes@kcl.ac.uk.
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.affiliation: Psychosis Studies, King's College London, London, United Kingdom; MRC Clinical Sciences Centre, Imperial College Hammersmith Hospital, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McCutcheon
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Psychosis Studies, King's College London, London, United Kingdom.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000150:complications; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D012565:Schizophrenic Psychology; D013315:Stress, Psychological / Q000150:complications*
chemical_list: C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: Dopamine; Etiology; Genetics; Neuroimaging; PET; Prodrome; Psychosis; Schizophrenia; Stress