Centre for Addiction and Mental Health, Toronto, ON, Canada.
Pharmacol Res. 2013 Apr;70(1):66-71. doi: 10.1016/j.phrs.2013.01.002. Epub 2013 Jan 14.
We showed previously, using [(3)H]-(+)-4-propyl-9-hydroxynaphthoxazine ([(3)H]-(+)-PHNO) autoradiography, that several antipsychotic drugs do not occupy dopamine D3 receptors at clinically-relevant doses in rat. This is an unexpected finding considering the near-equivalent in vitro affinity of these drugs for D2 and D3 receptors. The purpose of the current study was to address two possible methodological limitations of our previous report, namely that (1) [(3)H]-(+)-PHNO may have been administered at non-tracer dose, potentially causing underestimate of D3 receptor occupancy, and (2) antipsychotic drugs were administered chronically, potentially causing increased D3 receptor expression not accounted for in the vehicle-treated control group. We found that decreasing [(3)H]-(+)-PHNO dose from 5.6nmol/kg (our previous dose) to 0.6nmol/kg caused a >60% increase in [(3)H]-(+)-PHNO binding to D3 receptors in cerebellar lobes 9 and 10, indicating that our previous study was indeed conducted under non-tracer dose conditions. However, neither reducing [(3)H]-(+)-PHNO dose further to 0.3nmol/kg (a tracer dose), nor administering antipsychotics acutely affected antipsychotic receptor occupancy. At clinically-relevant levels of D2 occupancy (57-82% inhibition of striatal binding), neither olanzapine nor haloperidol occupied D3 receptors, while clozapine occupied D3 receptors at levels similar to our previous report (33%). Risperidone moderately occupied D3 receptors (40%), but at a dose occupying >90% of D2 receptors and therefore of questionable clinical relevance. These findings demonstrate that the lack of antipsychotic occupancy of D3 receptors is not attributable to limitations of our previous study. These results suggest that D3 receptor blockade is not necessary for the therapeutic effects of the antipsychotic drugs examined.
我们之前曾使用 [(3)H]-(+)-4-丙基-9-羟基萘并恶嗪 ([(3)H]-(+)-PHNO) 放射自显影技术表明，几种抗精神病药物在临床相关剂量下不会占据大鼠的多巴胺 D3 受体。考虑到这些药物与 D2 和 D3 受体的体外亲和力几乎相等，这是一个出人意料的发现。本研究的目的是解决我们之前报告中的两个可能的方法学限制，即 (1) [(3)H]-(+)-PHNO 可能已在非示踪剂量下给药，可能导致 D3 受体占有率低估，以及 (2) 抗精神病药物慢性给药，可能导致未在载体处理对照组中考虑到的 D3 受体表达增加。我们发现，将 [(3)H]-(+)-PHNO 剂量从 5.6nmol/kg（我们之前的剂量）降低到 0.6nmol/kg，会导致小脑叶 9 和 10 中 [(3)H]-(+)-PHNO 与 D3 受体的结合增加 >60%，表明我们之前的研究确实是在非示踪剂量条件下进行的。然而，进一步将 [(3)H]-(+)-PHNO 剂量降低到 0.3nmol/kg（示踪剂量），或急性给予抗精神病药物，都不会影响抗精神病药物受体占有率。在临床相关的 D2 占有率水平（纹状体结合的 57-82%抑制）下，奥氮平或氟哌啶醇都不占据 D3 受体，而氯氮平占据 D3 受体的水平与我们之前的报告相似（33%）。利培酮适度占据 D3 受体（40%），但在占据 >90% D2 受体的剂量下，因此具有可疑的临床相关性。这些发现表明，抗精神病药物缺乏对 D3 受体的占据并不是由于我们之前研究的限制。这些结果表明，D3 受体阻断对于所研究的抗精神病药物的治疗效果不是必需的。
