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Psychopharmacology

, Volume 234, Issue 3, pp 323–328 | Cite as

Measurement of psychological state changes at low dopamine transporter occupancy following a clinical dose of mazindol

  • Y. KimuraEmail author
  • J. Maeda
  • M. Yamada
  • K. Takahata
  • K. Yokokawa
  • Y. Ikoma
  • C. Seki
  • H. Ito
  • M. Higuchi
  • T. Suhara
Original Investigation

Abstract

Rationale

The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated.

Objectives

The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol.

Methods

Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding.

Results

Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24–25 %, and the binding potential of [11C]raclopride was reduced by 2.8–4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum.

Conclusions

A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness.

Keywords

Dopamine Dopamine transporters Positron emission tomography Mazindol Raclopride Fe-PE2I Consciousness Psychological state 

Notes

Acknowledgments

We thank Takahiro Shiraishi, Hironobu Fujiwara, Fumitoshi Kodaka, Harumasa Takano, and the other members of the Clinical Neuroimaging Team for their support with the PET scans, Izumi Kaneko-Izumida for the preparation of mazindol and the placebo, Kazuko Suzuki for assistance as the clinical research coordinator, Mika Omatsu, Hiromi Sano, and Takako Aoki for performing MRI scanning, and the staff of the Molecular Probe Program for the successful preparation of the radioligands.

This study was partly supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Japan Agency for Medical Research and Development, AMED.

Compliance with ethical standards

The study was approved by the Ethics and Radiation Safety Committee of the National Institute of Radiologic Sciences, Chiba, Japan and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all subjects before their inclusion in the study.

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Chait LD, Uhlenhuth EH, Johanson CE (1986) The discriminative stimulus and subjective effects of phenylpropanolamine, mazindol and d-amphetamine in humans. Pharmacol Biochem Behav 24:1665–1672CrossRefPubMedGoogle Scholar
  2. Chait LD, Uhlenhuth EH, Johanson CE (1987) Reinforcing and subjective effects of several anorectics in normal human volunteers. J Pharmacol Exp Ther 242:777–783PubMedGoogle Scholar
  3. Coakley JH, Edwards RH, Moorcraft J et al (1988) Mazindol in Duchenne muscular dystrophy. Lancet 1:184CrossRefPubMedGoogle Scholar
  4. Delaet D, Schauer D (2011) Obesity in adults. BMJ Clin Evid 03:604Google Scholar
  5. Dittrich A (1994) Psychological aspects of altered states of consciousness of the LSD type: measurements of their basic dimensions and prediction of individual differences. In: Pletscher A, Ladewig D (eds) 50 years of LSD. Current status and perspectives of hallucinogens. Pletscher A, New York, pp. 101–118Google Scholar
  6. Dittrich A (1998) The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry 31(Suppl 2):80–84CrossRefPubMedGoogle Scholar
  7. Drevets WC, Gautier C, Price JC et al (2001) Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry 49:81–96CrossRefPubMedGoogle Scholar
  8. Engstrom RG, Kelly LA, Gogerty JH (1975) The effects of 5-hydroxy-5(4′-chlorophenyl)-2, 3-dihydro-5H-imidazo (2, 1-a) isoindole (mazindol, SaH 42-548) on the metabolism of brain norepinephrine. Arch Int Pharmacodyn Ther 214:308–321PubMedGoogle Scholar
  9. Gatley SJ, Volkow ND, Gifford AN et al (1997) Model for estimating dopamine transporter occupancy and subsequent increases in synaptic dopamine using positron emission tomography and carbon-11-labeled cocaine. Biochem Pharmacol 53:43–52CrossRefPubMedGoogle Scholar
  10. Ichise M, Liow J-S, Lu J-Q et al (2003) Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cerebr Blood F Met 23:1096–1112CrossRefGoogle Scholar
  11. Kodaka F, Ito H, Kimura Y et al (2013) Test-retest reproducibility of dopamine D2/3 receptor binding in human brain measured by PET with [11C]MNPA and [11C]raclopride. Eur J Nucl Med Mol Imaging 40:574–579CrossRefPubMedGoogle Scholar
  12. Koepp MJ, Gunn RN, Lawrence AD et al (1998) Evidence for striatal dopamine release during a video game. Nature 393:266–268CrossRefPubMedGoogle Scholar
  13. Konofal E, Zhao W, Laouenan C et al (2014) Pilot phase II study of mazindol in children with attention deficit/hyperactivity disorder. Drug Des Devel Ther 8:2321–2332PubMedPubMedCentralGoogle Scholar
  14. Laruelle MA (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cerebr Blood F Met 20:423–451CrossRefGoogle Scholar
  15. Malison RT, McCance E, Carpenter LL et al (1998) [123I]β-CIT SPECT imaging of dopamine transporter availability after mazindol administration in human cocaine addicts. Psychopharmacology 137:321–325CrossRefPubMedGoogle Scholar
  16. Nakajima N, Hayashi H, Takahashi K et al (1986) Chronic toxicity test of mazindol in rats by oral 26-week administration. Clin Rep (JPN) 20:2243–2278Google Scholar
  17. Nittur N, Konofal E, Dauvilliers Y et al (2013) Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. Sleep Med 14:30–36CrossRefPubMedGoogle Scholar
  18. Preston KL, Sullivan JT, Berger P, Bigelow GE (1993) Effects of cocaine alone and in combination with mazindol in human cocaine abusers. J Pharmacol Exp Ther 267:296–307PubMedGoogle Scholar
  19. Sakayori T, Tateno A, Arakawa R et al (2014) Effect of mazindol on extracellular dopamine concentration in human brain measured by PET. Psychopharmacology 231:2321–2325CrossRefPubMedGoogle Scholar
  20. Tsukada H, Nishiyama S, Kakiuchi T et al (1999) Is synaptic dopamine concentration the exclusive factor which alters the in vivo binding of [11C]raclopride?: PET studies combined with microdialysis in conscious monkeys. Brain Res 841:160–169CrossRefPubMedGoogle Scholar
  21. Tziortzi AC, Haber SN, Searle GE et al (2014) Connectivity-based functional analysis of dopamine release in the striatum using diffusion-weighted MRI and positron emission tomography. Cereb Cortex 24:1165–1177CrossRefPubMedGoogle Scholar
  22. Volkow ND, Wang GJ, Fischman MW et al (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830CrossRefPubMedGoogle Scholar
  23. Volkow ND, Wang G-J, Fowler JS et al (2002) Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 43:181–187CrossRefPubMedGoogle Scholar
  24. Volkow ND, Fowler JS, Logan J et al (2009) Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA 301:1148–1154CrossRefPubMedPubMedCentralGoogle Scholar
  25. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A et al (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902CrossRefPubMedGoogle Scholar
  26. Vollenweider FX, Vontobel P, Hell D, Leenders KL (1999) 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride. Neuropsychopharmacology 20:424–433CrossRefPubMedGoogle Scholar
  27. Yanagida T, Wakasa Y, Oinuma N (1982) Drug dependence potential of mazindol tested in rhesus monkeys. Gent Inst Exp Anim Preclin Rep (JPN) 8:247–257Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Functional Brain Imaging Research, National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and TechnologyChibaJapan
  2. 2.Department of Clinical and Experimental Neuroimaging Center for Development of Advanced Medicine for DementiaNational Center for Geriatrics and GerontologyObuJapan
  3. 3.Precursory Research for Embryonic Science and TechnologyJapan Science and Technology AgencySaitamaJapan
  4. 4.Department of Molecular Imaging and TheranosticsNational Institute of Radiological Sciences National Institutes for Quantum and Radiological Science and TechnologyChibaJapan
  5. 5.Department of Radiology and Nuclear MedicineFukushima Medical UniversityFukushimaJapan

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