Rupniak N M, Hall M D, Mann S, Fleminger S, Kilpatrick G, Jenner P, Marsden C D
Biochem Pharmacol. 1985 Aug 1;34(15):2755-63. doi: 10.1016/0006-2952(85)90577-5.
Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.
已对大鼠长期（长达12个月）给予氟哌啶醇或氯氮平对脑多巴胺功能的影响进行了比较。在用氟哌啶醇（1.4 - 1.6毫克/千克/天）治疗1 - 12个月的大鼠中，出现了无目的的咀嚼颌部运动。这些运动仅在氯氮平（24 - 27毫克/千克/天）治疗12个月后才观察到。在氟哌啶醇治疗12个月期间，阿扑吗啡诱导的（0.125 - 0.25毫克/千克）刻板行为受到抑制。氯氮平治疗则无此效果。12个月后，高剂量阿扑吗啡（0.5 - 1.0毫克/千克）诱导的刻板行为在氟哌啶醇治疗的大鼠中增强，但在氯氮平治疗的大鼠中未增强。在氟哌啶醇给药的整个12个月期间，纹状体3H - 螺哌隆结合的最大结合容量（Bmax）升高，但氯氮平治疗未使其改变。纹状体3H - NPA结合的Bmax仅在氟哌啶醇治疗12个月后升高；氯氮平治疗无此效果。3H - 匹莫齐特结合的Bmax未因氟哌啶醇治疗而改变，但在氯氮平治疗9个月和12个月后升高。多巴胺（50微摩尔）刺激的腺苷酸环化酶活性在氟哌啶醇治疗1个月后受到抑制，但此后恢复正常。慢性氯氮平治疗未改变腺苷酸环化酶活性。在摄入氟哌啶醇或氯氮平3个月和12个月后，纹状体乙酰胆碱含量增加。这些发现表明，非典型抗精神病药物氯氮平的长期给药不会产生与典型抗精神病药物氟哌啶醇类似的脑多巴胺功能变化。特别是，与氟哌啶醇不同，氯氮平的长期给药似乎不会诱导纹状体D - 2受体超敏反应。出乎意料的是，与氟哌啶醇不同，氯氮平治疗改变了D - 1受体功能。
