Kim Sung Won, Fowler Joanna S, Skolnick Phil, Muench Lisa, Kang Yeona, Shea Colleen, Logan Jean, Kim Dohyun, Carter Pauline, King Payton, Alexoff David, Volkow Nora D
Laboratory of Neuroimaging,National Institute on Alcohol Abuse and Alcoholism,Upton, NY,USA.
Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
Int J Neuropsychopharmacol. 2014 Aug;17(8):1257-67. doi: 10.1017/S1461145714000194. Epub 2014 Mar 28.
Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [11C]PHNO and [11C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [11C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.
多巴胺D3受体（D3R）拮抗剂可能是治疗多种物质使用障碍（SUDs）的有效药物。然而，目前尚无选择性D3R拮抗剂可用于临床试验。丁螺环酮最初被鉴定为5-HT1A部分激动剂并用作抗焦虑药，它也以高亲和力与D3R和D4R结合，与D2R的亲和力较低，并能干扰可卡因奖赏效应。在此，我们使用正电子发射断层扫描（PET）以及[11C]PHNO（D3R优先放射性配体）、[11C]雷氯必利（D2R/D3R放射性配体）和[11C]NNC-112（D1R放射性配体）来测量口服和注射用丁螺环酮在灵长类动物脑中的占有率。肌肉注射丁螺环酮（0.19和0.5mg/kg）可阻断[11C]PHNO和[11C]雷氯必利与纹状体的结合，在15分钟时显示出高占有率（50 - 85%），并在2 - 6小时内快速清除。相比之下，口服丁螺环酮（3mg/kg）在3小时时显著阻断了富含D3R区域（苍白球和中脑）的[11C]PHNO结合，但对[11C]雷氯必利结合的影响极小（1小时时为28 - 37%，3小时时为10%）。丁螺环酮未阻断[11C]NNC-112。我们的研究结果表明，肌肉注射丁螺环酮可阻断D3R和D2R，而口服丁螺环酮在体内对D3R阻断更具选择性，这与广泛的首过代谢一致，并支持其代谢产物（5 - 和6'-羟基丁螺环酮）值得评估用于治疗SUDs的假说。这些结果还表明，对于口服丁螺环酮要实现大于80%的持续D3R占有率（这可能是治疗成瘾所需的），将需要比用于治疗焦虑的剂量（最大60mg）更高（至少三倍）的剂量。尽管如此，基于先前的临床研究，这些剂量将是安全且耐受性良好的。
