Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Neuropsychopharmacology. 2021 Nov;46(12):2112-2120. doi: 10.1038/s41386-021-01095-2. Epub 2021 Aug 4.
Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.
临床前研究支持多巴胺 D3 受体 (DRD3) 在酒精使用障碍 (AUD) 中的重要作用。在动物中，自愿饮酒会增加 DRD3 的表达，而药理学阻断 DRD3 可减轻酒精自我给药和酒精寻求的复燃。然而，这些发现尚未在人类中得到验证。本研究使用正电子发射断层扫描 (PET) 和 [C]-(+)-PHNO 比较了早期戒断的 AUD 受试者（n=17；戒断 6.59±4.14 天）和健康对照组（n=18）中几个多巴胺 D2 受体 (DRD2) 和 DRD3 感兴趣区域的受体水平。我们招募了符合 DSM-5 酒精使用障碍标准的非治疗寻求受试者。我们分别使用线索反应程序和静脉内酒精自我给药 (IVASA) 范式，检查了 DRD2/3 水平与酒精渴求以及酒精动机/渴望之间的关系。当联合观察所有 DRD2/3 ROI 时，AUD 受试者的 [C]-(+)-PHNO 结合水平明显低于 HC 的结合水平（Wilk's Λ=.58，F(6,28)=3.33，p=0.013，η=0.42），但没有区域特异性差异。结合值表明 SMST 和 SN 中的 [C]-(+)-PHNO 结合分别降低了-12.3%和-16.1%，尽管这些差异没有通过 Bonferroni 校正。在 APT 中，SN（几乎完全反映 DRD3）中的 [C]-(+)-PHNO 结合与 APT 中的α（较低的值反映了更高的酒精需求）之间存在正相关，在 Bonferroni 校正后（r=0.66，p=0.0080）。这表明 SN 中 DRD3 水平较低的 AUD 受试者表现出对酒精的需求增加。这些结果复制了先前的发现，证明了 DRD2/3 水平降低，同时也支持早期戒断的 AUD 中 DRD3 上调和潜在下调。此外，SN 中结合物与酒精需求相关的发现值得进一步研究。
