Measurement of psychological state changes at low dopamine transporter occupancy following a clinical dose of mazindol
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.
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.
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.
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.
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.
Trial registration https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009703
KeywordsDopamine Dopamine transporters Positron emission tomography Mazindol Raclopride Fe-PE2I Consciousness Psychological state
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.
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