CoChat
Sign Up
Cited by 1,291Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorParkinson's Disease Mechanisms and Treatments

Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects

Open access
Laruelle, M, Abi-Dargham, A, van Dyck, C H, Gil, R, D'Souza, C D, Erdos, J, McCance, E, Rosenblatt, W +7 more·1996·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.93.17.9235PMC PMC38625
Open this paper in CoChat — free account

Abstract

The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZM binding potential was associated with emergence or worsening of positive psychotic symptoms. This result suggests that psychotic symptoms elicited in this experimental setting in schizophrenic patients are associated with exaggerated stimulation of dopaminergic transmission. Such an observation would be compatible with an abnormal responsiveness of dopaminergic neurons in schizophrenia.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.93.17.9235

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 Laruelle et al., 1996

    The Abstract reports greater amphetamine-induced dopamine release in the striatum of patients with schizophrenia than in controls, associated with emergence or worsening of positive psychotic symptoms. It does not establish elevated baseline dopamine availability during acute psychosis or describe this as the most widely replicated abnormality. The epilepsy finding is attached to a different citation in the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. Angrist B. M., Gershon S. The phenomenology of experimentally induced amphetamine psychosis--preliminary observations. Biol Psychiatry. 1970 Apr;2(2):95–107. [PubMed] [Google Scholar]
  2. Azzaro A. J., Rutledge C. O. Selectivity of release of norepinephrine, dopamine and 5-hydroxytryptamine by amphetamine in various regions of rat brain. Biochem Pharmacol. 1973 Nov 15;22(22):2801–2813. doi: 10.1016/0006-2952(73)90147-0. [DOI] [PubMed] [Google Scholar] · DOI
  3. Benes F. M., McSparren J., Bird E. D., SanGiovanni J. P., Vincent S. L. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 1991 Nov;48(11):996–1001. doi: 10.1001/archpsyc.1991.01810350036005. [DOI] [PubMed] [Google Scholar] · DOI
  4. Burt D. R., Creese I., Snyder S. H. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science. 1977 Apr 15;196(4287):326–328. doi: 10.1126/science.847477. [DOI] [PubMed] [Google Scholar] · DOI
  5. Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1988 Sep;1(3):179–186. doi: 10.1016/0893-133x(88)90012-7. [DOI] [PubMed] [Google Scholar] · DOI
  6. Cross A. J., Crow T. J., Ferrier I. N., Johnstone E. C., McCreadie R. M., Owen F., Owens D. G., Poulter M. Dopamine receptor changes in schizophrenia in relation to the disease process and movement disorder. J Neural Transm Suppl. 1983;18:265–272. [PubMed] [Google Scholar]
  7. Davis K. L., Kahn R. S., Ko G., Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991 Nov;148(11):1474–1486. doi: 10.1176/ajp.148.11.1474. [DOI] [PubMed] [Google Scholar] · DOI
  8. Deutch A. Y. Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease. J Neural Transm Gen Sect. 1993;91(2-3):197–221. doi: 10.1007/BF01245232. [DOI] [PubMed] [Google Scholar] · DOI
  9. Dewey S. L., Smith G. S., Logan J., Brodie J. D. Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates. Neuropsychopharmacology. 1993 Jun;8(4):371–376. doi: 10.1038/npp.1993.37. [DOI] [PubMed] [Google Scholar] · DOI
  10. Farde L., Nordström A. L., Wiesel F. A., Pauli S., Halldin C., Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992 Jul;49(7):538–544. doi: 10.1001/archpsyc.1992.01820070032005. [DOI] [PubMed] [Google Scholar] · DOI
  11. Farde L., Wiesel F. A., Stone-Elander S., Halldin C., Nordström A. L., Hall H., Sedvall G. D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. Arch Gen Psychiatry. 1990 Mar;47(3):213–219. doi: 10.1001/archpsyc.1990.01810150013003. [DOI] [PubMed] [Google Scholar] · DOI
  12. Gandelman M. S., Baldwin R. M., Zoghbi S. S., Zea-Ponce Y., Innis R. B. Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: beta-CIT, IBF, and iomazenil. J Pharm Sci. 1994 Jul;83(7):1014–1019. doi: 10.1002/jps.2600830718. [DOI] [PubMed] [Google Scholar] · DOI
  13. Green A. L., el Hait M. A. Inhibition of mouse brain monoamine oxidase by (+)-amphetamine in vivo. J Pharm Pharmacol. 1978 Apr;30(4):262–263. doi: 10.1111/j.2042-7158.1978.tb13223.x. [DOI] [PubMed] [Google Scholar] · DOI
  14. Hietala J., Syvälahti E., Vuorio K., Någren K., Lehikoinen P., Ruotsalainen U., Räkköläinen V., Lehtinen V., Wegelius U. Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography. Arch Gen Psychiatry. 1994 Feb;51(2):116–123. doi: 10.1001/archpsyc.1994.03950020040004. [DOI] [PubMed] [Google Scholar] · DOI
  15. Horn A. S., Coyle J. T., Snyder S. H. Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons. Mol Pharmacol. 1971 Jan;7(1):66–80. [PubMed] [Google Scholar]
  16. Ichikawa J., Meltzer H. Y. The effect of chronic atypical antipsychotic drugs and haloperidol on amphetamine-induced dopamine release in vivo. Brain Res. 1992 Mar 6;574(1-2):98–104. doi: 10.1016/0006-8993(92)90805-j. [DOI] [PubMed] [Google Scholar] · DOI
  17. Innis R. B., Malison R. T., al-Tikriti M., Hoffer P. B., Sybirska E. H., Seibyl J. P., Zoghbi S. S., Baldwin R. M., Laruelle M., Smith E. O. Amphetamine-stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates. Synapse. 1992 Mar;10(3):177–184. doi: 10.1002/syn.890100302. [DOI] [PubMed] [Google Scholar] · DOI
  18. Karreman M., Moghaddam B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem. 1996 Feb;66(2):589–598. doi: 10.1046/j.1471-4159.1996.66020589.x. [DOI] [PubMed] [Google Scholar] · DOI
  19. Kay S. R., Fiszbein A., Opler L. A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  20. Kung H. F., Kasliwal R., Pan S. G., Kung M. P., Mach R. H., Guo Y. Z. Dopamine D-2 receptor imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N- [(1-ethyl-2-pyrrolidinyl)methyl]benzamide. J Med Chem. 1988 May;31(5):1039–1043. doi: 10.1021/jm00400a027. [DOI] [PubMed] [Google Scholar] · DOI
  21. Köhler C., Fuxe K., Ross S. B. Regional in vivo binding of [3H]N-propylnorapomorphine in the mouse brain. Evidence for labelling of central dopamine receptors. Eur J Pharmacol. 1981 Jul 10;72(4):397–402. doi: 10.1016/0014-2999(81)90584-7. [DOI] [PubMed] [Google Scholar] · DOI
  22. Laruelle M., Abi-Dargham A., van Dyck C. H., Rosenblatt W., Zea-Ponce Y., Zoghbi S. S., Baldwin R. M., Charney D. S., Hoffer P. B., Kung H. F. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med. 1995 Jul;36(7):1182–1190. [PubMed] [Google Scholar]
  23. Lee T., Seeman P., Tourtellotte W. W., Farley I. J., Hornykeiwicz O. Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature. 1978 Aug 31;274(5674):897–900. doi: 10.1038/274897a0. [DOI] [PubMed] [Google Scholar] · DOI
  24. Lidow M. S., Goldman-Rakic P. S., Rakic P., Innis R. B. Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6412–6416. doi: 10.1073/pnas.86.16.6412. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  25. Lidsky T. I. Reevaluation of the mesolimbic hypothesis of antipsychotic drug action. Schizophr Bull. 1995;21(1):67–74. doi: 10.1093/schbul/21.1.67. [DOI] [PubMed] [Google Scholar] · DOI
  26. Lieberman J. A., Kane J. M., Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987;91(4):415–433. doi: 10.1007/BF00216006. [DOI] [PubMed] [Google Scholar] · DOI
  27. Lieberman J. A., Kinon B. J., Loebel A. D. Dopaminergic mechanisms in idiopathic and drug-induced psychoses. Schizophr Bull. 1990;16(1):97–110. doi: 10.1093/schbul/16.1.97. [DOI] [PubMed] [Google Scholar] · DOI
  28. Logan J., Dewey S. L., Wolf A. P., Fowler J. S., Brodie J. D., Angrist B., Volkow N. D., Gatley S. J. Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: comparison of simulations and experimental results from PET studies in baboons. Synapse. 1991 Nov;9(3):195–207. doi: 10.1002/syn.890090306. [DOI] [PubMed] [Google Scholar] · DOI
  29. Martinot J. L., Paillère-Martinot M. L., Loc'h C., Hardy P., Poirier M. F., Mazoyer B., Beaufils B., Mazière B., Allilaire J. F., Syrota A. The estimated density of D2 striatal receptors in schizophrenia. A study with positron emission tomography and 76Br-bromolisuride. Br J Psychiatry. 1991 Mar;158:346–350. doi: 10.1192/bjp.158.3.346. [DOI] [PubMed] [Google Scholar] · DOI
  30. Meltzer H. Y. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 1989;99 (Suppl):S18–S27. doi: 10.1007/BF00442554. [DOI] [PubMed] [Google Scholar] · DOI
  31. Nordström A. L., Farde L., Eriksson L., Halldin C. No elevated D2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methylspiperone. Psychiatry Res. 1995 Aug 8;61(2):67–83. doi: 10.1016/0925-4927(95)02732-d. [DOI] [PubMed] [Google Scholar] · DOI
  32. Pilowsky L. S., Costa D. C., Ell P. J., Verhoeff N. P., Murray R. M., Kerwin R. W. D2 dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients. An 123I-IBZM single photon emission computerised tomography study. Br J Psychiatry. 1994 Jan;164(1):16–26. doi: 10.1192/bjp.164.1.16. [DOI] [PubMed] [Google Scholar] · DOI
  33. Reith J., Benkelfat C., Sherwin A., Yasuhara Y., Kuwabara H., Andermann F., Bachneff S., Cumming P., Diksic M., Dyve S. E. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11651–11654. doi: 10.1073/pnas.91.24.11651. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  34. Retaux S., Besson M. J., Penit-Soria J. Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex. Neuroscience. 1991;43(2-3):323–329. doi: 10.1016/0306-4522(91)90296-z. [DOI] [PubMed] [Google Scholar] · DOI
  35. Ross S. B., Jackson D. M. Kinetic properties of the accumulation of 3H-raclopride in the mouse brain in vivo. Naunyn Schmiedebergs Arch Pharmacol. 1989 Jul;340(1):6–12. doi: 10.1007/BF00169199. [DOI] [PubMed] [Google Scholar] · DOI
  36. Schwarz R. D., Uretsky N. J., Bianchine J. R. The relationship between the stimulation of dopamine synthesis and release produced by amphetamine and high potassium in striatal slices. J Neurochem. 1980 Nov;35(5):1120–1127. doi: 10.1111/j.1471-4159.1980.tb07867.x. [DOI] [PubMed] [Google Scholar] · DOI
  37. Seeman P. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse. 1987;1(2):133–152. doi: 10.1002/syn.890010203. [DOI] [PubMed] [Google Scholar] · DOI
  38. Seibyl J. P., Woods S. W., Zoghbi S. S., Baldwin R. M., Dey H. M., Goddard A. W., Zea-Ponce Y., Zubal G., Germine M., Smith E. O. Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM. J Nucl Med. 1992 Nov;33(11):1964–1971. [PubMed] [Google Scholar]
  39. Tune L. E., Wong D. F., Pearlson G., Strauss M., Young T., Shaya E. K., Dannals R. F., Wilson A. A., Ravert H. T., Sapp J. Dopamine D2 receptor density estimates in schizophrenia: a positron emission tomography study with 11C-N-methylspiperone. Psychiatry Res. 1993 Dec;49(3):219–237. doi: 10.1016/0165-1781(93)90063-m. [DOI] [PubMed] [Google Scholar] · DOI
  40. Uretsky N. J., Snodgrass S. R. Studies on the mechanism of stimulation of dopamine synthesis by amphetamine in striatal slices. J Pharmacol Exp Ther. 1977 Sep;202(3):565–580. [PubMed] [Google Scholar]
  41. Van Kammen D. P., Murphy D. L. Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment. Psychopharmacologia. 1975 Nov 21;44(3):215–224. doi: 10.1007/BF00428897. [DOI] [PubMed] [Google Scholar] · DOI
  42. Volkow N. D., Wang G. J., Fowler J. S., Logan J., Schlyer D., Hitzemann R., Lieberman J., Angrist B., Pappas N., MacGregor R. Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse. 1994 Apr;16(4):255–262. doi: 10.1002/syn.890160402. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  43. Weinberger D. R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987 Jul;44(7):660–669. doi: 10.1001/archpsyc.1987.01800190080012. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  44. Wong D. F., Wagner H. N., Jr, Tune L. E., Dannals R. F., Pearlson G. D., Links J. M., Tamminga C. A., Broussolle E. P., Ravert H. T., Wilson A. A. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986 Dec 19;234(4783):1558–1563. doi: 10.1126/science.2878495. [DOI] [PubMed] [Google Scholar] · DOI
  45. van Rossum J. M. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther. 1966 Apr;160(2):492–494. [PubMed] [Google Scholar]
  46. van der Werf J. F., Sebens J. B., Vaalburg W., Korf J. In vivo binding of N-n-propylnorapomorphine in the rat brain: regional localization, quantification in striatum and lack of correlation with dopamine metabolism. Eur J Pharmacol. 1983 Feb 18;87(2-3):259–270. doi: 10.1016/0014-2999(83)90336-9. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., D'Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., Baldwin, R. M., Seibyl, J. P., Krystal, J. H., Charney, D. S., & Innis, R. B.
Affiliations
  • Yale University (US)
  • Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1996-08-20
Volume
93
Issue
17
Pages
9235-9240
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.93.17.9235
PMC
PMC38625
OpenAlex
W1996327177
Cited by
1,291
References
2
Citations by year
2026: 12 · 2025: 16 · 2024: 25 · 2023: 26 · 2022: 17 · 2021: 19 · 2020: 31 · 2019: 33 · 2018: 26 · 2017: 38 · 2016: 36 · 2015: 44 · 2014: 57 · 2013: 58 · 2012: 65
FWCI
23.33
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Yale University
  • National Alliance for Research on Schizophrenia and Depression
  • U.S. Public Health Service
  • National Institute of Mental Health (MH-54192, R01MH054192)
  • National Center for Research Resources (M01RR000125, M01 RR-00125)
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, dopamine release, amphetamine challenge, dopamine D2 receptor, [123I]IBZM, striatum, dopamine hypothesis of schizophrenia, positive psychotic symptoms, dopamine signaling, SPECT imaging
MeSH terms
Adult, Amphetamine, Animals, Benzamides, Corpus Striatum, Dopamine, Female, Humans, Male, Papio, Psychoses, Substance-Induced, Pyrrolidines, Schizophrenia, Tomography, Emission-Computed, Single-Photon, Receptors, Dopamine D2, Dopamine Antagonists

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review