Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method
Open accessAbstract
A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outflow. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D2/D3 positron-emission tomography radioligand [11C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n = 4), doubling the amphetamine dose produced a doubling in [11C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg/kg) was 44:1, demonstrating that relatively small binding changes reflect large changes in dopamine outflow. In the clinical study, patients with schizophrenia (n = 11) compared with healthy volunteers (n = 12) had significantly greate…
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The most widely replicated dopaminergic abnormality in schizophrenia is elevated striatal dopamine availability in acute psychoses of both schizophrenia and epilepsy.
“The most widely replicated abnormality is that of elevated striatal dopamine availability – in acute psychoses of both schizophrenia (Laruelle et al., 1996; Breier et al., 1997) and epilepsy (Reith et al., 1994).”
From The Computational Anatomy of Psychosis (2013) · cites this paper as Breier et al., 1997
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“A limitation of these studies is that, although the changes in [(11)C]raclopride binding are linearly related to extracellular DA in animal experiments (Breier et al., 1997), the precise relationship with synaptic DA is not understood.”
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“Dopamine transmission in patients with schizophrenia has been investigated in many studies using the paradigm described above (Abi-Dargham et al., 1998 ; Breier et al., 1997 ; Laruelle et al., 1999).”
MethodNeurobiology of Dopamine in Schizophrenia
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BackgroundMethodSex differences in striatal dopamine release in healthy adults.
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Mechanism of action of methylphenidate: Insights from PET imaging studies
Volkow, N. D., Fowler, J. S., Wang, G., Ding, Y., & Gatley, S. J. (2002) · Journal of Attention Disorders · doi:10.1177/070674370200601s05 · Cited by 353 · see citing works
Martinez, D., Narendran, R., Foltin, R. W., Slifstein, M., Hwang, D.-R., Broft, A., Huang, Y., Cooper, T. B., Fischman, M. W., Kleber, H. D., et al. (2007) · American Journal of Psychiatry · doi:10.1176/ajp.2007.164.4.622 · Cited by 351 · see citing works
“It should be noted that amphetamine, rather than cocaine, was chosen for challenge because amphetamine can be administered to healthy subjects and since the correlation between dopamine and radiotracer displacement has been established in microdialysis studies on nonhuman primates (30, 31).”
BackgroundKaar, S., Natesan, S., McCutcheon, R., & Howes, O. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107704 · Cited by 348 · see citing works
Anatomical Substrates for Glutamate‐Dopamine Interactions
Sesack, S., Carr, D. B., Omelchenko, N., & Pinto, A. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1300.066 · Cited by 348 · see citing works
The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia
Tseng, K. Y., Chambers, R. A., & Lipska, B. K. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.11.039 · Cited by 336 · see citing works
Laruelle, M. (2000) · Brain research. Brain research reviews · doi:10.1016/s0165-0173(99)00054-5 · Cited by 347 · see citing works
Lindström, L., Gefvert, O., Hagberg, G., Lundberg, T., Bergström, M., Hartvig, P., & Långström, B. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00109-2 · Cited by 332 · see citing works
Waltz, J. A., & Gold, J. M. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.03.010 · Cited by 331 · see citing works
“Schizophrenia has also been associated with excessive dopaminergic tone in the basal ganglia (Breier et al., 1997; Abi-Dargham et al., 1998), along with reduced stimulus-evoked activity in the ventral striatum (Juckel et al.”
BackgroundVolkow, N. D., Wang, G.-J., Newcorn, J., Telang, F., Solanto, M. V., Fowler, J. S., Logan, J., Ma, Y., Schulz, K., Pradhan, K., et al. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.8.932 · Cited by 331 · see citing works
“First, although changes in [(11)C]raclopride binding are related to extracellular DA, the precise relationship with extracellular DA is not understood.(33,53) The poor temporal resolution of PET allowed us to detect DA changes only over a 20- to 30-minute period, reflecting mostly tonic DA activity, and thus we could…”
BackgroundDopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience
Kesby, J., Eyles, D., McGrath, J., & Scott, J. G. (2018) · Translational Psychiatry · doi:10.1038/s41398-017-0071-9 · Cited by 331 · see citing works
Models of schizophrenia in humans and animals based on inhibition of NMDA receptors.
Bubeníková-Valešová, V., Horáček, J., Vrajová, M., & Höschl, C. (2008) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.03.012 · Cited by 330 · see citing works
“Similar changes in the glutamatergic and dopaminergic systems were found in patients with schizophrenia (Kim et al., 1980; Tsai et al., 1995; Breier et al., 1997).”
ResultDopamine release in human ventral striatum and expectation of reward.
de la Fuente-Fernández, R., Phillips, A., Zamburlini, M., Sossi, V., Calne, D., Ruth, T. J., & Stoessl, A. (2002) · Behavioural Brain Research · doi:10.1016/s0166-4328(02)00130-4 · Cited by 329 · see citing works
Volkow, N. D., Wang, G., Fowler, J. S., Logan, J., Franceschi, D., Maynard, L., Ding, Y., Gatley, S. J., Gifford, A., Zhu, W., et al. (2002) · Synapse · doi:10.1002/syn.10038 · Cited by 321 · see citing works
“These relatively small changes reflect the limited sensitivity of the [11C]raclopride displacement method; it has been estimated that an 8-fold increase in extracellular DA will decrease [11C]raclopride specific binding by less than 1% (Breier et al., 1997).”
BackgroundInfluentialKrystal, J. H., Perry, E. B., Gueorguieva, R., Belger, A., Madonick, S. H., Abi-Dargham, A., Cooper, T. B., MacDougall, L., Abi-Saab, W., & D’Souza, D. C. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.9.985 · Cited by 317 · see citing works
“This study used a relatively high dose of amphetamine, in the range that worsened psychosis in patients diagnosed as having schizophrenia.(28,29) As a result, a relatively low subanesthetic dose of ketamine was used to minimize the cardiovascular risk to the research participants.”
ResultImaging studies on the role of dopamine in cocaine reinforcement and addiction in humans
Volkow, N. D., Fowler, J. S., & Wang, G.-J. (1999) · Journal of Psychopharmacology · doi:10.1177/026988119901300406 · Cited by 315 · see citing works
“induced by psychostimulants as assessed with microdialysis and those obtained using PET or SPECT (Breier et al., 1997; Laruelle et al., 1997a).”
BackgroundMethodInfluentialMcCutcheon, R., Beck, K., Jauhar, S., & Howes, O. D. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx180 · Cited by 305 · see citing works
Boileau, I., Dagher, A., Leyton, M., Gunn, R. N., Baker, G. B., Diksic, M., & Benkelfat, C. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.12.1386 · Cited by 305 · see citing works
Video Games and Rehabilitation: Using Design Principles to Enhance Engagement in Physical Therapy
Lohse, K., Shirzad, N., Verster, A., Hodges, N., & der Loos, H. F. M. V. (2013) · Journal of Neurologic Physical Therapy · doi:10.1097/npt.0000000000000017 · Cited by 305 · see citing works
Reviewing the ketamine model for schizophrenia
Frohlich, J., & Van Horn, J. D. (2014) · Journal of Psychopharmacology · doi:10.1177/0269881113512909 · Cited by 303 · see citing works
“This enhanced sensitivity to the dopaminergic effects of amphetamine challenge is also characteristic of schizophrenia patients, as revealed by PET and SPECT imaging (Breier et al., 1997; Laruelle et al., 1996).”
ResultMolecular imaging of the dopaminergic system and its association with human cognitive function.
Cropley, V., Fujita, M., Innis, R., & Nathan, P. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.004 · Cited by 299 · see citing works
Neurotransmitter interactions in schizophrenia–therapeutic implications
Carlsson, A., Waters, N., & Carlsson, M. L. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00117-1 · Cited by 298 · see citing works
Schizophrenia: from phenomenology to neurobiology
Wong, A. H. C., & Tol, H. H. M. V. (2003) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(03)00035-6 · Cited by 282 · see citing works
“[103] Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D.”
BackgroundTowards a muscarinic hypothesis of schizophrenia
Raedler, T., Bymaster, F., Tandon, R., Copolov, D., & Dean, B. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001924 · Cited by 289 · see citing works
Gerber, D., Sotnikova, T. D., Gainetdinov, R., Huang, S., Caron, M., & Tonegawa, S. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.261583798 · Cited by 282 · see citing works
Volkow, N. D., Wang, G.-J., Fowler, J. S., Telang, F., Maynard, L., Logan, J., Gatley, S. J., Pappas, N., Wong, C., Vaska, P., et al. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.7.1173 · Cited by 281 · see citing works
“We used PET imaging with [11C]raclopride, a dopamine D2 receptor ligand sensitive to competition with endogenous dopamine (10), to measure the relative changes in extracellular dopamine induced by methylphenidate when administered before the mathematical task and before the neutral task.”
BackgroundMethodSchizophrenia: More dopamine, more D <sub>2</sub> receptors
Seeman, P., & Kapur, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.14.7673 · Cited by 279 · see citing works
Pathway-specific dopamine abnormalities in schizophrenia
Weinstein, J., Chohan, M. O., Slifstein, M., Kegeles, L., Moore, H., & Abi-Dargham, A. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.03.2104 · Cited by 275 · see citing works
“Using D2 radiotracers and a psychostimulant challenge, four studies showed higher release in the striatum of antipsychotic-free (Rx-free) patients compared to healthy controls (HC) (52-55).”
Ettinger, U., Meyhöfer, I., Steffens, M., Wagner, M., & Koutsouleris, N. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00018 · Cited by 272 · see citing works
“Imaging studies have shown that patients with schizophrenia, both in the acute phase and in remission, show amphetamine-induced reductions in D2 and D3 dopamine receptor binding potential in the striatum (177, 178).”
Background
- Authors
- Breier, A., Su, T.-P., Saunders, R., Carson, R. E., Kolachana, B. S., de Bartolomeis, A., Weinberger, D. R., Weisenfeld, N., Malhotra, A. K., Eckelman, W. C., & Pickar, D.
- Affiliations
- National Institutes of Health (US)
- Experimental Therapeutics Branch and Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; and Clinical Center Positron-Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-03-18
- Volume
- 94
- Issue
- 6
- Pages
- 2569-2574
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC20129
- OpenAlex
- W2150760506
- Cited by
- 1,154
- References
- 43
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 19 · 2023: 9 · 2022: 17 · 2021: 22 · 2020: 20 · 2019: 26 · 2018: 29 · 2017: 27 · 2016: 34 · 2015: 35 · 2014: 44 · 2013: 51 · 2012: 54
- FWCI
- 36.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- schizophrenia, synaptic dopamine, amphetamine, [11C]raclopride, striatum, dopamine release, microdialysis, non-human primates
- MeSH terms
- Amphetamine, Animals, Carbon Radioisotopes, Corpus Striatum, Dopamine, Humans, Macaca mulatta, Reference Values, Regression Analysis, Salicylamides, Schizophrenia, Synapses, Tomography, Emission-Computed, Microdialysis, Raclopride
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