Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.
Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.
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DOI：
10.1523/jneurosci.4371-11.2012
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发表时间：
2012-01-25
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影响因子：
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通讯作者：
Kish SJ
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作者：
Boileau I;Payer D;Houle S;Behzadi A;Rusjan PM;Tong J;Wilkins D;Selby P;George TP;Zack M;Furukawa Y;McCluskey T;Wilson AA;Kish SJ
正电子发射断层扫描（PET）的发现表明，兴奋剂使用者大脑中的D2型多巴胺受体和多巴胺浓度较低，这促使人们猜测，增加多巴胺信号可能有助于药物治疗。然而，这一策略需要考虑的可能性，根据动物和死后的人类数据，多巴胺能活性在相关的D3受体可能，相反，被升高，从而有助于吸毒行为。我们使用PET和D3偏好配体[11 C]-（+）-PHNO测试了甲基苯丙胺（MA）多药使用者中D3受体结合高于正常水平的假设。16名对照受试者和16名报告MA为主要滥用药物的多药使用者在[11 C]-（+）-PHNO后接受PET扫描。与对照组相比，吸毒者在富含D3的中脑黑质中有更高的[11 C]-（+）-PHNO结合（SN，+46%，p<0.02）和苍白球（+9%，p=0.06）和腹侧苍白球（+11%，p=0.1），而在富含D2的背侧纹状体中结合率略低（~-4%，NS;重度使用者为-12%，p=0.01），并与药物使用严重程度相关。MA使用者中富含D3的SN与富含D2的背侧纹状体中的[11 C]-（+）-PHNO结合率高出55%（p=0.004），重度使用者但非中度使用者的比率与对照组显着不同。SN中的[11 C]-（+）-PHNO结合与自我报告的“药物需求”相关。我们的结论是，多巴胺D3受体，不像D2受体，可能是上调的大脑中的MA多药使用者，虽然较低的多巴胺水平在MA用户可能有贡献的发现。需要进行药理学研究，以确定D3受体功能正常化是否可以降低兴奋剂滥用复发的脆弱性。
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]-(+)-PHNO. Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning following [11C]-(+)-PHNO. Compared to 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 (~−4%, NS; −12% in heavy users, p=0.01) and related to drug-use severity. [11C]-(+)-PHNO binding ratio in D3-rich SN vs. 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.