Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates.
Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates.
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DOI：
10.1016/j.biopsych.2014.06.012
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发表时间：
2015-03-01
影响因子：
10.6
通讯作者：
Bradberry CW
中科院分区：
文献类型：
--
作者：
Narendran R;Jedema HP;Lopresti BJ;Mason NS;Himes ML;Bradberry CW
与尸检数据一致，在最近的正电子发射断层扫描（PET）研究中，我们证明与对照组相比，可卡因滥用者的[11 C]-（+）-α-二氢丁苯那嗪（DTBZ）与纹状体囊泡单胺转运体2型（VMAT 2）结合较少。这些组间比较人类研究的一个主要局限性是他们无法建立可卡因滥用和较低VMAT 2之间的因果关系。此外，在可卡因自我给药前后评估VMAT 2结合的啮齿动物研究不支持VMAT 2减少。为了澄清这些不一致的VMAT 2结果，并将VMAT 2减少归因于可卡因滥用，我们在可卡因自我给药16个月前后对4只恒河猴进行了[11 C]DTBZ PET成像。纹状体中的[11 C]DTBZ结合电位（BPND）是使用简化的参考组织方法，以枕叶皮质时间活动曲线作为输入函数推导出来的。长期可卡因自我给药导致[11 C]DTBZ BPND显著降低（25.8 ± 7.8%）。与不支持VMAT 2改变的可卡因啮齿动物研究相反，非人灵长类动物中的这些结果清楚地表明，长期暴露于可卡因后VMAT 2结合减少。较低的VMAT 2意味着在突触前末梢中可用于释放的多巴胺储存囊泡较少，这可能是导致可卡因依赖中多巴胺传递减少的一个因素。未来的研究应试图阐明可卡因滥用者中较低VMAT 2的临床意义，例如，其与复发和易患情绪障碍的关系。
Consistent with postmortem data, in a recent positron emission tomography (PET) study, we demonstrated less [11C]-(+)-α-dihydrotetrabenazine (DTBZ) binding to striatal vesicular monoamine transporter, type 2 (VMAT2) in cocaine abusers compared to controls. A major limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Furthermore, studies in rodents that evaluated VMAT2 binding before and after cocaine selfadministration do not support a reduction in VMAT2. To clarify these discrepant VMAT2 findings and attribute VMAT2 reduction to cocaine abuse, we imaged four rhesus monkeys with [11C]DTBZ PET before and after 16-months of cocaine self-administration. [11C]DTBZ binding potential (BPND) in the striatum was derived using the simplified reference tissue method with the occipital cortex time activity curve as an input function. Chronic cocaine self-administration led to a significant (25.8 ± 7.8%) reduction in [11C]DTBZ BPND. In contrast to the cocaine rodent investigations that do not support alterations in VMAT2, these results in nonhuman primates clearly demonstrate a reduction in VMAT2 binding following prolonged exposure to cocaine. Lower VMAT2 implies that fewer dopamine storage vesicles are available in the pre-synaptic terminals for release, a likely factor contributing to decreased dopamine transmission in cocaine dependence. Future studies should attempt to clarify the clinical significance of lower VMAT2 in cocaine abusers, for example, its relationship to relapse and vulnerability to mood disorders.
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