Ishikane T, Kusumi I, Matsubara R, Matsubara S, Koyama T
Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.
Eur J Pharmacol. 1997 Feb 26;321(2):163-9. doi: 10.1016/s0014-2999(96)00948-x.
We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptors, while that with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D2 receptor up-regulation, Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT2A receptors are highly occupied compared with dopamine D2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.
我们研究了血清素能活性对氟哌啶醇诱导的大鼠纹状体多巴胺D2受体上调的调节作用。长期给予氟哌啶醇（0.1、0.5mg/kg，腹腔注射，3周）可增加多巴胺D2受体数量，而非典型抗精神病药物氯氮平（10mg/kg）和反式-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂环庚并[4,5-c]吡咯烷马来酸盐（ORG 5222；0.25mg/kg）则未观察到增加。长期给予非选择性5-羟色胺（5-羟色胺，5-HT）受体激动剂6-氯-2-(1-哌嗪基)吡嗪（MK-212，2.5mg/kg）或5-HT再摄取抑制剂西酞普兰（10mg/kg）可增强氟哌啶醇（0.1mg/kg）诱导的多巴胺D2受体上调，而5-HT1A受体激动剂(±)-8-羟基-2-(二正丙基氨基)四氢萘（8-OH-DPAT，0.1mg/kg）对多巴胺D2受体上调无影响。5-HT2A/2C受体拮抗剂利坦色林（1mg/kg）与低剂量氟哌啶醇（0.1mg/kg）合用可减弱多巴胺D2受体上调，但与高剂量氟哌啶醇（0.5mg/kg）合用则无此作用。急性给予氟哌啶醇（0.1mg/kg）加用利坦色林（1mg/kg）后，体内使用N-乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ）检测到的5-HT2A和多巴胺D2受体占有率分别为69.8%和45.1%。这种5-HT2A受体占有率高于多巴胺D2受体的情况与氯氮平或ORG 5222相似。这些结果表明，强效的5-HT2A受体拮抗作用与弱的多巴胺D2受体阻断作用可能与氯氮平或ORG 5222长期治疗后多巴胺D2受体未上调有关。
