Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C] -(+)-Propyl-Hexahydro-Naphtho-Oxazin in Methamphetamine Polydrug Users: A Positron Emission Tomography Study

Positron emission tomography (PET) findings suggesting lower D-2-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 D-3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D-3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D-3-preferring ligand [(CH)-C-11[-(+)-propyl-hexahydro-naphtho-oxazin ([C-11]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [C-11](+)-PHNO. Compared with control subjects, drug users had higher [C-11](+)-PHNO binding in the D-3-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 D-2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p = 0.01) and related to drug-use severity. The [C-11]-(+)-PHNO binding ratio in D-3-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. [C-11]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D-3 receptor, unlike the D-2 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 D-3 receptor function could reduce vulnerability to relapse in stimulant abuse.