title: Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.
abstract: Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.
authors.affiliation: Addiction Imaging Research Group, Vivian M. Rakoff PET Imaging Centre, Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8. isabelle_boileau@camh.net
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boileau
authors.forename: Doris
authors.initials: D
authors.lastname: Payer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Arian
authors.initials: A
authors.lastname: Behzadi
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Rusjan
authors.forename: Junchao
authors.initials: J
authors.lastname: Tong
authors.forename: Diana
authors.initials: D
authors.lastname: Wilkins
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.forename: Tony P
authors.initials: TP
authors.lastname: George
authors.forename: Martin
authors.initials: M
authors.lastname: Zack
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Tina
authors.initials: T
authors.lastname: McCluskey
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes / Q000378:metabolism; D015259:Dopamine Agents / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008694:Methamphetamine / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000000981:diagnostic imaging* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C043445:4-propyl-7-hydroxy-1,2,3,4a,5,6-hexahydronaphthoxazine; D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D008024:Ligands; D010078:Oxazines; D050637:Receptors, Dopamine D3; D008694:Methamphetamine