Tarazi F I, Shirakawa O, Tamminga C A
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore 21228.
Eur J Pharmacol. 1993 Feb 23;232(1):71-7. doi: 10.1016/0014-2999(93)90730-6.
The effect of a highly selective dopamine D2 receptor antagonist, raclopride ((-)-(S)-3,5-dichloro-N-(1-ethyl-2-pyrrolidinyl) methyl-6-methoxysalicylamide tartrate), on regional cerebral glucose metabolism in rat brain was determined using [14C]2-deoxyglucose autoradiography, and compared to a typical neuroleptic, haloperidol. Based on preclinical biochemistry and early clinical trial reports, it was hypothesized that raclopride would fail to functionally affect brain regions putatively involved with motor function, while altering psychosis-related regions. Raclopride at a low dose (1.5 mg/kg) significantly reduced regional cerebral glucose metabolism in neocortical areas. It showed a trend toward a similar reduction in limbic structures. But the drug did not have an effect in the extrapyramidal system at this dose. While, at a higher dose, raclopride (10.0 mg/kg), significantly reduced regional glucose metabolism throughout the susceptible grey matter areas of the brain including extrapyramidal regions, an effect similar to haloperidol. Based on approximate antipsychotic dose equivalence between haloperidol and raclopride, the clinically relevant low dose used in this study, failed to functionally alter metabolism in motor regions of brain while exerting a haloperidol-like effect in other areas traditionally linked to cognitive and affective behaviors. This suggests that a low dose of raclopride can exert regionally selective actions. The high dose of raclopride is metabolically active in all brain areas, and, therefore, in clinical application might produce involuntary motor syndromes, like parkinsonism and late onset dyskinesias, along with its antipsychotic effects.
使用[14C]2-脱氧葡萄糖放射自显影技术测定了高选择性多巴胺D2受体拮抗剂雷氯必利（(-)-(S)-3,5-二氯-N-(1-乙基-2-吡咯烷基)甲基-6-甲氧基水杨酰胺酒石酸盐）对大鼠脑区局部脑葡萄糖代谢的影响，并与典型抗精神病药物氟哌啶醇进行了比较。基于临床前生物化学和早期临床试验报告，推测雷氯必利在功能上不会影响假定与运动功能有关的脑区，而会改变与精神病相关的脑区。低剂量（1.5 mg/kg）的雷氯必利显著降低了新皮质区域的局部脑葡萄糖代谢。在边缘结构中也有类似降低的趋势。但该剂量的药物对外锥体系没有影响。而高剂量（10.0 mg/kg）的雷氯必利显著降低了包括锥体外区域在内的整个脑易感灰质区域的局部葡萄糖代谢，这一作用与氟哌啶醇相似。基于氟哌啶醇和雷氯必利之间近似的抗精神病等效剂量，本研究中使用的临床相关低剂量未能在功能上改变脑运动区域的代谢，而在传统上与认知和情感行为相关的其他区域发挥了类似氟哌啶醇的作用。这表明低剂量的雷氯必利可发挥区域选择性作用。高剂量的雷氯必利在所有脑区均具有代谢活性，因此在临床应用中可能会在产生抗精神病作用的同时，引发帕金森症和迟发性运动障碍等不自主运动综合征。
