title: Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans.
abstract: There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.
authors.affiliation: Translational Addiction Research Laboratory, Toronto, ON, Canada.|Addiction Program Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Pharmacology, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.affiliation: Addiction Program Centre for Addiction and Mental Health, Toronto, ON, Canada.|Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Doris
authors.initials: D
authors.lastname: Payer
authors.affiliation: Translational Addiction Research Laboratory, Toronto, ON, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Di Ciano
authors.affiliation: Translational Addiction Research Laboratory, Toronto, ON, Canada.
authors.forename: Mihail
authors.initials: M
authors.lastname: Guranda
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Multimodal Imaging Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Division of Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Addiction Program Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
authors.affiliation: Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mansouri
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Mood and Anxiety Disorders Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Meyer
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Multimodal Imaging Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Division of Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
authors.affiliation: Addiction Program Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.|Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boileau
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002065:Buspirone / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D004244:Dizziness / Q000139:chemically induced / Q000378:metabolism; D015259:Dopamine Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D049268:Positron-Emission Tomography; D011388:Prolactin / Q000097:blood; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D016037:Single-Blind Method; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide; D011388:Prolactin; D002065:Buspirone