5-羟色胺与氯氮平致糖脂代谢紊乱的相关性探讨

目的 通过研究非典型性抗精神病药氯氮平单用及与5-羟色胺合用对小鼠糖脂代谢的影响,探讨氯氮平致糖脂紊乱与5-羟色胺之间的关系.方法 42只雄性小鼠随机分为6组,分别为空白组、氯氮平4 mg/kg组、氯氮平20 mg/kg组、5-HT 20 mg/kg组、氯氮平4 mg/kg+5-HT 20mg/kg组和氯氮平20 mg/kg+5-HT 20 mg/kg组,分别于给药1周和4周时测定小鼠的空腹血糖和糖耐量,4周后测定小鼠血清甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C)、血清胰岛素(Ins)和空腹血糖(FBG).结果 (1)单用氯氮平20 mg/kg可使小鼠糖耐量、TG、LDL-C、TC和HO-MA-IR水平升高,降低HDL-C水平.(2)5-羟色胺与氯氮平联用可改善糖耐量,显著降低单用氯氮平导致的TG、LDL-C、TC和HOMA-1R水平,同时升高HDL-C水平.结论 氯氮平导致的小鼠糖脂代谢紊乱可能与其抑制5-羟色胺受体有关.     

氯氮平对谷氨酸功能低下精神分裂症小鼠模型的作用

目的 观察氯氮平对地卓西平马来酸盐（MK-801）所致谷氨酸功能低下精神分裂症小鼠模型的高活动性及刻板行为的作用。方法 昆明种小鼠130只。（1）取34只小鼠分为4组：溶媒空白对照组（腹腔注射溶媒，以下简称对照组）；3种氯氮平剂量（1．0，1．5，2．0mg／kg体质量，腹腔注射）组；每组8～10只，观察氯氮平对小鼠探究行为和自主活动的影响。（2）取46只小鼠分为5组，分别为对照组、MK-801模型组（溶媒＋MK-801，0．25mg／kg体质量，腹腔注射）及3种剂量（同上）氯氮平组分别加MK-801（0．25mg／kg体质量，腹腔注射），每组8～10只，观察氯氮平对MK-致801小鼠自主活动增加的影响。（3）取50只小鼠，每组10只，给药方案同“（2）”，观察氯氮平对MK-801引起的刻板行为的影响。结果 （1）与对照组比较，氯氮平剂量为1．5mg／kg体质量和2．0mg／kg体质量时，小鼠的探究行为及自主活动总路程减少（P均〈0．001）；但剂量为1．0mg／kg时，对小鼠的探究行为及自主活动均无影响（P均〉0．05）。（2）氯氮平剂量为1．0～2．0mg／kg体质量时，呈剂量依赖性抑制由MK-801引起的自主活动增加（均P〈0．05）。（3）氯氮平剂量为1．5～2．0mg／kg体质量时，呈剂量依赖性抑制MK-801引起的刻板行为（均P〈0．05）。但低剂量（1．0mg／kg体质量）氯氮平对MK-801引起的刻板行为无明显影响（P〉0．05）。结论 氯氮平对MK-801所致谷氨酸功能低下精神分裂症小鼠模型不同脑区的作用有选择性，低剂量时抑制由中脑边缘、中脑皮质系统介导的高活动性，较高剂量时抑制由中脑边缘、中脑皮质系统及黑质纹状体系统控制的高活动性及刻板行为。     

Hormonal correlates of clozapine-induced weight gain in psychotic children: an exploratory study

OBJECTIVE: Weight gain is a serious side effect of atypical antipsychotics, especially in childhood. In this study, the authors examined six weight gain-related hormones in patients with childhood-onset schizophrenia (COS) after 6 weeks of clozapine treatment. METHOD: Fasting serum samples for 24 patients with COS and 21 matched healthy controls (HC) were obtained. Levels of leptin, insulin, adiponectin, amylin, ghrelin, and tumor necrosis factor alpha were measured and compared between the groups. For 23 patients with COS, hormonal levels were measured at background and week 6 of clozapine treatment. Change in body mass index was correlated with levels of clozapine and changes in hormonal levels and clinical ratings. RESULTS: At baseline, COS did not differ significantly from HC on any hormonal measure. Clozapine treatment was associated with significant (7.9% +/- 8.5%) increase in mean body mass index. Only leptin levels increased significantly from baseline to week 6 on clozapine (p = .003). Body mass index increase was significantly correlated with decrease in ghrelin and adiponectin and was positively correlated with clinical improvement. CONCLUSIONS: This is the first study of weight gain-related hormones in children on clozapine. Hormonal changes are correlated with weight gain. How effectiveness of clozapine is linked to weight gain remains uncertain.     

不同浓度氯氮平对小鼠空腹血糖和骨骼肌葡萄糖转运蛋白4基因表达的影响

目的探讨氯氮平对雄性C57BL/6小鼠空腹血糖和骨骼肌葡萄糖转运蛋白4(GLUT4)基因表达的影响。方法将63只雄性C57BL/6小鼠随机分为3组,每组21只,分别灌胃给予蒸馏水、氯氮平4mg/kg及氯氮平20mg/kg,于给药后3h、1周、4周以试纸法测定各组空腹血糖,用逆转录-聚合酶链反应测定GLUT4mRNA表达。结果(1)灌药后3h、1周氯氮平4mg/kg组和氯氮平20mg/kg组空腹血糖和GLUT4mRNA的表达与空白对照组相比,差异无统计学意义(P>0.05);(2)灌药后4周氯氮平4mg/kg组和20mg/kg组的空腹血糖值[(5.6±0.5)mmol/L和(5.8±0.5)mmol/L]高于空白对照组[(4.6±0.6)mmol/L],而GLUT4mRNA的表达(0.50±0.14和0.48±0.12)却低于空白对照组(0.85±0.27),差异均有统计学意义(P<0.01)。结论氯氮平可以慢性升高空腹血糖,降低GLUT4mRNA的表达,可能是抗精神病药长期应用后血糖升高的发生机制之一。     

No evidence for association of alpha 1a adrenoceptor gene polymorphism and clozapine-induced urinary incontinence

Clozapine is an effective atypical antipsychotic that has high affinity for many neurotransmitter receptors. Among the adverse effects of clozapine, urinary incontinence is commonly found and is suggested to be caused by alpha-adrenergic blockade. We tested the hypothesis that clozapine-induced urinary incontinence is related to a genetic variant of the alpha(1a)-adrenoceptor. We also tested whether the alpha(1a)-receptor gene confers susceptibility to schizophrenic disorders. Our result indicated that the alpha(1a)-adrenoceptor gene polymorphism investigated plays no major role in the pathogenesis of schizophrenia or in clozapine-induced urinary incontinence. Considering the superior effects of clozapine and its potent adrenergic antagonistic effects, it is of interest to investigate the association between this polymorphism and the treatment response.     

Clozapine inhibits development and expression of nicotine-induced locomotor sensitization in rats

It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.     

第二代抗精神病药对大鼠血糖、胰岛素和C肽分泌的影响

目的 了解第二代抗精神病药(氯氨平、奥氮平、喹硫平、阿立哌唑)对大鼠体重、空腹血糖、胰岛素和C肽分泌的影响.方法 25只雌性SD(Sprague Dawley,SD)大鼠随机均分成5组.分别给予氯氮平20 mg/(kg·d)、奥氮平5 mg/(kg·d)、喹硫平20 mg/(kg·d)、阿立哌唑5mg/(kg·d)和生理盐水灌胃,共28 d.在第1、7、14、28天分别剪尾采血,测体重及空腹血糖,于第28天测定空腹血浆胰岛素和C肽水平.结果 适应性喂养1周后,5组大鼠的空腹血糖和体重水平差异无统计学意义(P＞0.05).持续灌胃第14及28天,氯氮平、奥氮平和喹硫平组空腹血糖高于空白时照组(P＜0.05);持续灌胃28 d,氯氮平、奥氮平组的体重高于空白对照组(P＜0.05);与未加处理因素前(第1天)相比,氯氮平、奥氮平和喹硫平组体重和空腹血糖随时间的延长而增加(P＜0.05),而阿立哌哇组的变化无统计学意义(P＞0.05).持续灌胃第28天,氯氮平、奥氮平和喹硫平组空腹血浆胰岛素和C肽水平高于空白对照组(P＜0.05);而阿立哌唑组变化不明显(P＞0.05).结论 氯氮平、奥氮平、喹硫平可引起大鼠胰岛素抵抗和血糖代谢异常.     

Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat

The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195+/-12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p<0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p<0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia.     

Clozapine-induced neutropenia in children: management with lithium carbonate

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.     

Clozapine improves dizocilpine-induced delayed alternation impairment in rats

Summary The effects of systemic administration of dizocilpine (0.16mg/kg, i.p.), clozapine (7.5mg/kg, s.c.) and coadministration of dizocilpine (0.16mg/ kg, i.p.) and clozapine (7.5mg/kg, s.c.) on acquisition of delayed alternation in a T-maze were tested in rats (N=7 per group) on six days with 10 choices per day and animal. Clozapine given alone did not impair delayed alternation learnint, except of the first day. Dizocilpine induced a significant delayed alternation impairment on all days tested. Pretreatment with clozapine significantly improved the dizocilpine-induced impairment. Treatment-induced changes of delayed alternation learning and of locomotor activities showed no correlation. The results demonstrate that clozapine functionally compensated for deficits induced by a blockade of the N-methyl-D-asparatate (NMDA) subtype of glutamate receptors.