Ichikawa J, Meltzer H Y
Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio.
J Pharmacol Exp Ther. 1991 Jan;256(1):348-57.
The differential effects of haloperidol (HAL) and clozapine (CLOZ) on dopamine (DA) release and metabolism (dihydroxyphenylacetic acid levels) in striatum and nucleus accumbens (accumbens) of freely moving rats were investigated using microdialysis. Chronic HAL (2 mg/kg/day x 21 days in drinking water) decreased basal DA release and metabolism in both regions, and produced tolerance to HAL-induced increase in DA metabolism in striatum. No modification of HAL-induced increases in DA release and metabolism were observed in accumbens. Together with D2 receptor blockade, this may produce decreased dopaminergic neurotransmission in both regions during chronic treatment. Chronic HAL (0.5 mg/kg/day x 21 days in drinking water) also decreased basal DA release and metabolism in both regions which were not reversed by 25 micrograms/kg of (-)-apomorphine, s.c. In marked contrast, chronic CLOZ (20 mg/kg/day x 21 days in drinking water) had no effect on basal DA release and metabolism in either region, whereas it produced tolerance to CLOZ-induced increase in DA release and metabolism in accumbens. Together with weak D2 receptor blockade, this may lead to slightly decreased dopaminergic neurotransmission in accumbens and slightly increased dopaminergic neurotransmission in striatum during chronic CLOZ treatment. These differences may contribute to the clinical differences between the two agents.
使用微透析技术研究了氟哌啶醇（HAL）和氯氮平（CLOZ）对自由活动大鼠纹状体和伏隔核中多巴胺（DA）释放及代谢（二羟基苯乙酸水平）的不同影响。慢性给予HAL（2毫克/千克/天，在饮用水中持续21天）可降低这两个区域的基础DA释放及代谢，并使纹状体中HAL诱导的DA代谢增加产生耐受性。在伏隔核中未观察到HAL诱导的DA释放及代谢增加有改变。与D2受体阻断一起，这可能在慢性治疗期间导致两个区域的多巴胺能神经传递减少。慢性给予HAL（0.5毫克/千克/天，在饮用水中持续21天）也降低了这两个区域的基础DA释放及代谢，皮下注射25微克/千克的（-）-阿扑吗啡不能使其恢复。与之形成鲜明对比的是，慢性给予CLOZ（20毫克/千克/天，在饮用水中持续21天）对任一区域的基础DA释放及代谢均无影响，而它使伏隔核中CLOZ诱导的DA释放及代谢增加产生耐受性。与较弱的D2受体阻断一起，这可能导致在慢性CLOZ治疗期间伏隔核中的多巴胺能神经传递略有减少，而纹状体中的多巴胺能神经传递略有增加。这些差异可能导致这两种药物在临床上的差异。
