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The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia
Open accessAbstract
The dopamine hypothesis is the longest standing pathoaetiological theory of schizophrenia. As 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 impact on 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 DRD2 receptor and those involved in the up-stream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acid (GABA)-ergic 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 sensitise 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.
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Citations
Cites
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299
The physiology, signaling, and pharmacology of dopamine receptors
Beaulieu, J.-M., & Gainetdinov, R. R. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.002642 · Cited by 2,763
The NHGRI GWAS Catalog, a curated resource of SNP-trait associations
Welter, D., MacArthur, J., Morales, J., Burdett, T., Hall, P., Junkins, H., Klemm, A., Flicek, P., Manolio, T., Hindorff, L., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1229 · Cited by 2,707
Varese, F., Smeets, F., Drukker, M., Lieverse, R., Lataster, T., Viechtbauer, W., Read, J., van Os, J., & Bentall, R. P. (2012) · Schizophrenia Bulletin · doi:10.1093/schbul/sbs050 · Cited by 2,436
Cortical inhibitory neurons and schizophrenia
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1648 · Cited by 2,297
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
Popoli, M., Yan, Z., McEwen, B. S., & Sanacora, G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3138 · Cited by 1,393
Modelling schizophrenia using human induced pluripotent stem cells
Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., et al. (2011) · Nature · doi:10.1038/nature09915 · Cited by 1,375
Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group
Yung, A. R., Phillips, L. J., Yuen, H. P., Francey, S. M., McFarlane, C. A., Hallgren, M., & McGorry, P. D. (2003) · Schizophrenia Research · doi:10.1016/s0920-9964(02)00167-6 · Cited by 1,136
Schizophrenia: A neural diathesis-stress model.
Walker, E. F., & Diforio, D. (1997) · Psychological Review · doi:10.1037//0033-295x.104.4.667 · Cited by 930
Seeman, P., & Lee, T. (1975) · Science · doi:10.1126/science.1145194 · Cited by 869 · cited 1×
“Later, the potency of antipsychotics was linked to their affinity for dopamine D2 receptors - linking molecular action to clinical phenotype (7).”
Bilder, R. M., Volavka, J., Lachman, H. M., & Grace, A. A. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300542 · Cited by 769
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten, A. F. T. (2015) · Nature Neuroscience · doi:10.1038/nn.4087 · Cited by 752
Elevated Striatal Dopamine Function Linked to Prodromal Signs of Schizophrenia
Howes, O. D., Montgomery, A. J., Asselin, M.-C., Murray, R. M., Valli, I., Tabraham, P., Bramon-Bosch, E., Valmaggia, L., Johns, L., Broome, M., et al. (2009) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2008.514 · Cited by 744
Self-citationPruessner, J. C., Champagne, F., Meaney, M. J., & Dagher, A. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3422-03.2004 · Cited by 709
Glutamate and dopamine in schizophrenia: An update for the 21 st century
Howes, O., McCutcheon, R., & Stone, J. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881114563634 · Cited by 702
Self-citationDISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling
Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., et al. (2005) · Science · doi:10.1126/science.1112915 · Cited by 648 · cited 1×
“DISC1 is also involved in anchoring phosphodiesterase 4A (PDE4A) next to the spine apparatus (106).”
Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia
Kegeles, L. S., Abi-Dargham, A., Frankle, W. G., Gil, R., Cooper, T. B., Slifstein, M., Hwang, D.-R., Huang, Y., Haber, S. N., & Laruelle, M. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.10 · Cited by 565
McGlashan, T. H., Zipursky, R. B., Perkins, D., Addington, J., Miller, T., Woods, S. W., A. Hawkins, K., E. Hoffman, R., Preda, A., Epstein, I., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.5.790 · Cited by 556
Mizoguchi, K., Yuzurihara, M., Ishige, A., Sasaki, H., Chui, D.-H., & Tabira, T. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-04-01568.2000 · Cited by 481
Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R., Winter, C., Riva, M. A., Mortensen, P. B., Feldon, J., et al. (2013) · Science · doi:10.1126/science.1228261 · Cited by 459
Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [ 18 F]-DOPA PET Imaging Study
Howes, O. D., Bose, S. K., Turkheimer, F., Valli, I., Egerton, A., Valmaggia, L. R., Murray, R. M., & McGuire, P. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.11010160 · Cited by 343
Self-citationEvaluating historical candidate genes for schizophrenia
Farrell, M. S., Werge, T., Sklar, P., Owen, M. J., Ophoff, R. A., O'Donovan, M. C., Corvin, A., Cichon, S., & Sullivan, P. F. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.16 · Cited by 315
Self-citationHowes, O., Bose, S., Turkheimer, F., Valli, I., Egerton, A., Stahl, D., Valmaggia, L., Allen, P., Murray, R., & McGuire, P. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.20 · Cited by 292
Self-citationSchizophrenia: More dopamine, more D 2 receptors
Seeman, P., & Kapur, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.14.7673 · Cited by 279
Increased stress-induced dopamine release in psychosis
Mizrahi, R., Addington, J., Rusjan, P. M., Suridjan, I., Ng, A., Boileau, I., Pruessner, J. C., Remington, G., Houle, S., & Wilson, A. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.10.009 · Cited by 277
Selvaraj, S., Arnone, D., Cappai, A., & Howes, O. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.06.005 · Cited by 223
Self-citationEvidence-based pharmacotherapy of post-traumatic stress disorder (PTSD)
Ipser, J. C., & Stein, D. J. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001209 · Cited by 216
Abi-Dargham, A., van de Giessen, E., Slifstein, M., Kegeles, L. S., & Laruelle, M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.12.007 · Cited by 213
Howes, O. D., Williams, M., Ibrahim, K., Leung, G., Egerton, A., McGuire, P. K., & Turkheimer, F. (2013) · Brain · doi:10.1093/brain/awt264 · Cited by 198
Self-citationUrsini, G., Bollati, V., Fazio, L., Porcelli, A., Iacovelli, L., Catalani, A., Sinibaldi, L., Gelao, B., Romano, R., Rampino, A., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6631-10.2011 · Cited by 188 · cited 1×
“In Val homozygotes increased lifetime stress was found to correlate with reduced methylation that in turn correlated with poorer working memory performance (94).”
Gresch, P. J., Sved, A. F., Zigmond, M. J., & Finlay, J. M. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.63020575.x · Cited by 179
Ruhrmann, S., Bechdolf, A., Kühn, K.-U., Wagner, M., Schultze-Lutter, F., Janssen, B., Maurer, K., Häfner, H., Gaebel, W., Möller, H.-J., et al. (2007) · British Journal of Psychiatry · doi:10.1192/bjp.191.51.s88 · Cited by 150
Valenti, O., Gill, K. M., & Grace, A. A. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08038.x · Cited by 131
Abi-Dargham, A., Kegeles, L. S., Zea-Ponce, Y., Mawlawi, O., Martinez, D., Mitropoulou, V., O'Flynn, K., Koenigsberg, H. W., Van Heertum, R., Cooper, T., et al. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.01.018 · Cited by 128
Peciña, M., Mickey, B. J., Love, T., Wang, H., Langenecker, S. A., Hodgkinson, C., Shen, P.-H., Villafuerte, S., Hsu, D., Weisenbach, S. L., et al. (2013) · Cortex · doi:10.1016/j.cortex.2012.01.010 · Cited by 123
Oswald, L. M., Wand, G. S., Kuwabara, H., Wong, D. F., Zhu, S., & Brasic, J. R. (2014) · Psychopharmacology · doi:10.1007/s00213-013-3407-z · Cited by 114
Lataster, J., Collip, D., Ceccarini, J., Haas, D., Booij, L., van Os, J., Pruessner, J., Van Laere, K., & Myin-Germeys, I. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.07.030 · Cited by 109 · cited 2×
“Two PET studies with healthy volunteers demonstrated more widespread cortical displacement of a D2/3 radiotracer during a stress task relative to a control task (57,58) (Table 2).”
Mizrahi, R., Kenk, M., Suridjan, I., Boileau, I., George, T. P., McKenzie, K., Wilson, A. A., Houle, S., & Rusjan, P. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.347 · Cited by 101
Qin, S., Cousijn, H., Rijpkema, M., Luo, J., Franke, B., Hermans, E. J., & Fernández, G. (2012) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2012.00016 · Cited by 83 · cited 1×
“acute stress, Met homozygotes show impairments in working memory performance and reduced PFC activation, while Val carriers show the opposite effects (101; 102).”
Subtle gene-environment interactions driving paranoia in daily life
Simons, C. J. P., Wichers, M., Derom, C., Thiery, E., Myin‐Germeys, I., Krabbendam, L., & Van Os, J. (2009) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2008.00434.x · Cited by 82
Nagano-Saito, A., Dagher, A., Booij, L., Gravel, P., Welfeld, K., Casey, K. F., Leyton, M., & Benkelfat, C. (2013) · Synapse · doi:10.1002/syn.21700 · Cited by 60
Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
Gamo, N. J., Duque, A., Paspalas, C. D., Kata, A., Fine, R., Boven, L., Bryan, C., Lo, T., Anighoro, K., Bermudez, L., et al. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.104 · Cited by 37 · cited 1×
“Impairment of DISC1 reduces its ability to anchor PDE4A, and this in turn leads to a disinhibition of the stress response and accompanying PFC impairment (108).”
Positive association of Phencyclidine‐responsive genes, PDE4A and PLAT, with schizophrenia
Deng, X., Takaki, H., Wang, L., Kuroki, T., Nakahara, T., Hashimoto, K., Ninomiya, H., Arinami, T., Inada, T., Ujike, H., et al. (2011) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31233 · Cited by 21
Cited by
Dopamine: Functions, Signaling, and Association with Neurological Diseases
Klein, M. O., Battagello, D. S., Cardoso, A. R., Hauser, D. N., Bittencourt, J. C., & Correa, R. G. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0632-3 · Cited by 1,073
McCutcheon, R., Beck, K., Jauhar, S., & Howes, O. D. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx180 · Cited by 305
Self-citationThe Role of Estrogen in Brain and Cognitive Aging
Russell, J. K., Jones, C. K., & Newhouse, P. A. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00766-9 · Cited by 257
Onwordi, E. C., Halff, E. F., Whitehurst, T., Mansur, A., Cotel, M.-C., Wells, L., Creeney, H., Bonsall, D., Rogdaki, M., Shatalina, E., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14122-0 · Cited by 243
Self-citationJauhar, S., Nour, M. M., Veronese, M., Rogdaki, M., Bonoldi, I., Azis, M., Turkheimer, F., McGuire, P., Young, A. H., & Howes, O. D. (2017) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2017.2943 · Cited by 233
Self-citation
Metadata
- Authors
- Howes, O. D., McCutcheon, R., Owen, M. J., & Murray, R. M.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 81
- Issue
- 1
- Pages
- 9-20
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2486451269
- Cited by
- 601
- References
- 44
- FWCI
- 46.31
- Type
- journal article
- Language
- en
- Open access
- green
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