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Psychopharmacology

, Volume 173, Issue 1–2, pp 27–31 | Cite as

123I-β-CIT SPECT demonstrates increased presynaptic dopamine transporter binding sites in basal ganglia in vivo in schizophrenia

  • Hans SjøholmEmail author
  • Trond Bratlid
  • Johan Sundsfjord
Original Investigation

Abstract

Rationale

The dopamine hypothesis for schizophrenia postulates overactivity of dopamine transmission in the basal ganglia. Most effective antipsychotic drugs block postsynaptic dopamine receptors, but in-vivo imaging studies have not been able to show changes in these receptors in drug-naive schizophrenics.

Objectives

The presynaptic dopamine transporter (DAT) is thought to be an important regulator of synaptic dopamine concentration. We have used SPECT with 123I-β-CIT, which has a high affinity for DAT, in order to further examine the dopamine hypothesis for schizophrenia.

Methods

Six patients with chronic schizophrenia treated with classic dopamine D2-receptor blocking neuroleptics were investigated. The number of DAT binding sites in the basal ganglia was calculated and compared with five healthy volunteers and ten parkinsonian patients.

Results

The schizophrenic patients showed a 36–63% increase in DAT binding sites compared with the volunteers, whereas the parkinsonian patients showed a 57–96% decrease. The differences between the groups were highly significant (even after correction for different age composition within the groups).

Conclusions

There was an increased number of DAT binding sites in the schizophrenic patients treated with dopamine D2-receptor blocking neuroleptics. This fits well with several recent reports that have shown increased volumes of basal ganglia in this patient category. It thus appears that there is an increased number of presynaptic dopamine releasing nerve terminals in the basal ganglia, possibly as a biological adaptation to counteract the postsynaptic dopamine D2-receptor blockade.

Keywords

SPECT β-CIT Schizophrenia Dopamine Dopamine transporter 

Notes

Acknowledgements

The skillful technical support from engineer Torbjørn Jacobsen is gratefully acknowledged. The project was supported by a grant from the Norwegian Research Council.

References

  1. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–767PubMedGoogle Scholar
  2. Bannon MJ, Granneman JG, Kapatos G (1995) The dopamine transporter: potential involvement in neuropsychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, New YorkGoogle Scholar
  3. Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetaepinephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144Google Scholar
  4. Carlsson A, Hansson LO, Waters N, Carlsson ML (1997) Neurotransmitter aberrations in schizophrenia: new perspectives and therapeutic implications. Life Sci 61:75–94CrossRefPubMedGoogle Scholar
  5. Chakos MH, Lieberman JA, Bilder RM, Borenstein M, Lerner G, Bogerts B, Wu H, Kinon B, Ashtari M (1994) Increase in caudate volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry 151:1430–1436PubMedGoogle Scholar
  6. Chakos MH, Lieberman JA, Alvir J, Bilder R, Ashtari M (1995) Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 345:456–457CrossRefGoogle Scholar
  7. Corson PW, Nopoulos P, Miller DD, Arndt S, Andreasen NC (1999) Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 156:1200–1204PubMedGoogle Scholar
  8. Farde L, Wiesel FA, Halldin C, Sedwall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76PubMedGoogle Scholar
  9. Giros B, Jaber M, Jones SR, Wrightsman RM, Caron MG (1996) Hyperlocomotion and in-difference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612PubMedGoogle Scholar
  10. Gur RE, Maany V, Moxley D, Seanson C, Bilker W, Gur RC (1998) Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 155:1711–1717PubMedGoogle Scholar
  11. Innis RB, Seibyl JP, Scanly BE, Laruelle M, Abi-Dargham A, Wallace E, Baldwin RM, Zea-Ponce Y, Xoghbi S, Wang S, Gao Y, Neumayer JL, Charney DS, Hoffer PB, Marek KL (1993) Single photon computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson’s disease. Proc Natl Acad Sci USA 90:11965–11969PubMedGoogle Scholar
  12. Laakso A, Vilkman H, Alakare B, Haaparanta M, Bergman J, Solin O, Peurasaari J, Rakkolainen V, Syvalahti E, Hietala J (2000) Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography. Am J Psychiatry 157:269–271PubMedGoogle Scholar
  13. Laakso A, Bergman J, Haaparanta M, Vilkman H, Solin O, Syvalahti E, Hietala J (2001) Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia. Schizophr Res 52:115–120CrossRefPubMedGoogle Scholar
  14. Laruelle M, Baldwin RM, Malison RT, Zea-Ponce Y, Zoghbi SS, Al-tkriti MS, Sybirska EH, Zimerman R, Winniewski G, Neumeyer JL, Milius RA, Wang A, Smith EO, Roth RH, Charney DS, Hoffer PB, Innis RB (1993) SPECT imaging of dopamine and serotonine transporters with (123I) beta-CIT: pharmacological characterization of brain uptake in non-human primates. Synapse 13:295–309PubMedGoogle Scholar
  15. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, Dsouza CD, Erd J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computed tomography imaging of amphetamine-induced dopamie release in drug-free schizophrenic patients. Proc Natl Acad Sci USA 93:9235–9240PubMedGoogle Scholar
  16. Laruelle M, Abi-Dargham A, van Dyck C, Gil R, Dsouza DC, Krystal J, Seibyl J, Baldwin R, Innis RB (2000) Dopamine and serotonine transporters in patients with schizophrenia: an imaging study with (123I) beta-CIT. Biol Psychiatry 47:371–379CrossRefPubMedGoogle Scholar
  17. Nordstrom AL, Farde L, Eriksson L, Halldin C (1995) No elevated dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and (11C) N-metylspiperone. Psychiatry Res 61:67–83PubMedGoogle Scholar
  18. Nyberg S, Nordstrom AL, Halldin C, Farde L (1995) Positron emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man. Int Clin Psychopharmacol 10:81–85PubMedGoogle Scholar
  19. Randrup A, Munkvad I (1965) Special antagonism of amphetamine-induced abnormal behaviour. Psychopharmacologica 7:416–422Google Scholar
  20. Randrup A, Munkvad I (1967) Stereotyped activity produced by amphetamine in several animal species and man. Psychopharmacologica 11:300–310Google Scholar
  21. Shihabuddin L, Buchsbaum MS, Hazlett EA, Haznedar M,. Harvey PD, Newman A, Schnur DB, Spiegel-Cohen J, Wei T, Machac J, Lnesaurek K, Vallabhajosula S, Biten MA, Ciaravolu TM, Luu-Hsia C (1998) Dorsal striatal size, shape and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task. Arch Gen Psychiatry 55:235–243CrossRefPubMedGoogle Scholar
  22. Sjøholm H, Mellgren SI, Sundsfjord J (1997) Nigro-striatal degeneration demonstrated in parkinsonian patients with iodine-123-beta-CIT SPECT: methods of quantitation. Acta Neurol Scand 96:91–96PubMedGoogle Scholar
  23. Tonomi G, Edelmann GM (1998) Consciousness and complexity. Science 282:1846–1851PubMedGoogle Scholar
  24. Tuninger E, Levander S (1996) Large variations of plasma levels during maintenance treatment with depot neuroleptics. Br J Psychiatry 169:618–621PubMedGoogle Scholar
  25. van Dyck CH, Seibyl JP. Malison RT, Laruelle M, Zoghbi SS; Baldwin RM, Innis RB (2002) Age related decline in dopamine transporters: analysis of striatal subregions, nonlinear effects and hemispheric asymmetries. Am J Geriat Psychiatry 10:36–43CrossRefGoogle Scholar
  26. van Rossum JM (1966) The significance of dopamine receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn 160:492–494PubMedGoogle Scholar
  27. van Rossum JM (1967) The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Brill H, Cole JO, Deniker P, Hippius H, Bradley PB (eds) 5th Collegium Internationale Neuropsychopharmacologicum. Excerpta Medica, Amsterdam, pp 321–329Google Scholar
  28. Wagner HN, Burns DH, Dannals RF, Wong DF, Langstrom B, Duelfer D, Frost JJ, Raert HT, Links JM, Rosenblom SB, Lucas SE, Kramer AV, Kuhar MJ (1983) Imaging dopamine receptors in the human brain by positron tomography. Science 221:1264–1266PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Hans Sjøholm
    • 1
    • 4
    Email author
  • Trond Bratlid
    • 2
  • Johan Sundsfjord
    • 3
  1. 1.Department of NeurologyUniversity HospitalTromsøNorway
  2. 2.Department of PsychiatryUniversity HospitalTromsøNorway
  3. 3.Department of Nuclear MedicineUniversity HospitalTromsøNorway
  4. 4.Department of Clinical NeurophysiologyUllevål University HospitalOsloNorway

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