摘要目的:考察齐洛那平对不同精神分裂症动物模型的药效及其对多巴胺D 1、D 2等受体的体外亲和力。 方法:纳入雄性SPF级ICR小鼠324只，雄性SPF级Wistar 大鼠72只及SPF级SD大鼠雌雄各10只为研究对象。（1）取100只ICR小鼠分为10组：空白组（溶媒+生理盐水，简称Veh+NS），模型组（Veh+APO 1 mg/kg），利培酮（0.03、0.10、0.30、1.00 mg/kg，灌胃）+APO组，齐洛那平（0.3、1.0、3.0、10.0 mg/kg，灌胃）+APO组；每组10只，观察齐洛那平对小鼠攀爬行为的影响。（2）取84只ICR小鼠分为10组：空白组（Veh+NS），模型组（Veh+MK-801 0.3 mg/kg），利培酮（0.01、0.03、0.10、0.30 mg/kg，灌胃）+MK-801组，齐洛那平（0.3、1.0、3.0、10.0 mg/kg，灌胃）+MK-801组；每组8~10只，观察齐洛那平对MK-801诱导小鼠高活动行为的影响。（3）取70只ICR小鼠分为7组：空白组（Veh），利培酮0.3、1.0及3.0 mg/kg组（灌胃），齐洛那平15、27及45 mg/kg组（灌胃），每组10只，观察小鼠在给药后30、60 及90 min时保持僵住不动的时间。（4）取72只Wistar大鼠进行条件回避反应训练，将训练成功的大鼠分为7组：空白组（Veh），齐洛那平20、40及60 mg/kg组，利培酮0.2、0.4及0.8 mg/kg组，每组5~6只，考察齐洛那平对大鼠回避反应次数的影响。（5）取70只ICR小鼠，颈部皮下注射给予PCP（5 mg/kg）造模后，将小鼠分为空白组（Veh+NS），模型组（Veh+PCP），利培酮 0.05 mg/kg+PCP组，齐洛那平（0.5、1.0、2.0 mg/kg）+PCP组，每组10~12只，考察齐洛那平对PCP诱导小鼠新物体识别障碍的影响。（6）将20只SD大鼠（雌雄各半）断头取脑，并制备5-HT 2A及5-HT 2C受体膜，取表达CHO-D 1、D 2及5-HT 6受体的细胞株制备D 1、D 2及5-HT 6受体膜，通过放射性配体受体结合的实验方法，考察齐洛那平对D 1、D 2、5-HT 2A、5-HT 6及5-HT 2C的亲和力。组间计量资料比较采用单因素方差分析，计数资料采用非参数 U检验。 结果:（1）与模型组比较，齐洛那平剂量3.0及10.0 mg/kg可显著抑制APO诱导的小鼠攀爬行为（ Z=-3.43、-4.07，均 P<0.01），ED 50为4.31 mg/kg。利培酮剂量在0.10、0.30及1.00 mg/kg可显著抑制小鼠攀爬行为（ Z=-1.83、-2.48、-4.26， P<0.05或 P<0.01），ED 50为0.19 mg/kg。（2）与模型组比较，齐洛那平剂量3.0及10.0 mg/kg可显著抑制MK-801诱导的小鼠高活动行为（ t=-7.18、3.90，均 P<0.01），ED 50为2.63 mg/kg。利培酮0.01、0.03、0.10及0.30 mg/kg均显著抑制小鼠高活动行为（ t=-3.02、4.98、-6.08、7.10，均 P<0.01），ED 50为0.011 mg/kg。（3）齐洛那平及利培酮均可诱发小鼠产生僵住症，其ED 50分别为35.36 mg/kg及1.25 mg/kg。（4）齐洛那平以及利培酮均能剂量依赖性抑制大鼠的回避反应次数，与空白组比较，齐洛那平剂量在40及60 mg/kg时可显著性抑制大鼠条件回避反应次数（ t=11.84、13.07，均 P<0.01），ED 50为34.36 mg/kg；利培酮0.8 mg/kg可显著抑制大鼠条件回避反应次数（ t=13.50， P<0.01），ED 50为0.60 mg/kg。（5）与模型组比较，齐洛那平0.5及1.0 mg/kg给药时能显著改善PCP诱导的新物体识别障碍模型小鼠的区分指数（ t=-3.67、-2.12，均 P<0.05及 P<0.01），提高认知能力；而利培酮0.05 mg/kg对PCP诱导的新物体识别障碍模型小鼠的区分指数无显著性影响。（6）齐洛那平对D 1（K i=3.21 nmol/L）、5-HT 2A（K i=13.11 nmol/L）、5-HT 6（K i=21.49 nmol/L）及5-HT 2C（K i=48.90 nmol/L）受体有较高的亲和力，而对D 2（K i=563.20 nmol/L）受体亲和力较弱。利培酮对5-HT 2A、5-HT 2C和D 2受体具有较高亲和力，其K i分别为2.37、18.79和4.82 nmol/L，利培酮对D 1和5-HT 6亲和力较弱。 结论:齐洛那平对多个精神分裂症阳性症状动物模型均有较好的药效且能改善小鼠的认知，其体内药效活性可能与多巴胺D 1、D 2受体及5-HT 2A和5-HT 6受体有关。

abstractsObjective:To investigate the efficacy of zicronapine on different animal models of schizophrenia and its affinity for dopamine D1 and D2 receptors in vitro.Methods:A total of 324 male SPF ICR mice, 72 male SPF Wistar rats, and 10 male and female each SPF SD rats were included in the study. (1) One hundred ICR mice were divided into 10 groups: Blank group (solvent+normal saline, Veh+NS), model group (Veh+APO 1 mg/kg), risperidone (0.03, 0.10, 0.30, 1.00 mg/kg, gavage)+APO group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+APO group; The effect of zicronapine on the climbing behavior of mice was observed. (2) Eighty-four ICR mice were divided into 10 groups: Blank group (Veh+NS), model group (Veh+MK-801 0.3 mg/kg), risperidone (0.01, 0.03, 0.10, 0.30 mg/kg, gavage)+MK-801 group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+MK-801 group; 8-10 rats were allocated in each group to observe the effect of zicronapine on MK-801-induced hyperactivity behavior in mice. (3) Seventy mice were divided into 7 groups: Blank group (Veh), risperidone 0.3, 1.0 and 3.0 mg/kg groups (gavage), and zicronapine15, 27 and 45 mg/kg groups (gavage), with 10 mice in each group. The maintaining immobilized time of rats was observed at 30 min, 60 min and 90 min after administration. (4) A total of 72 Wistar rats were selected for CAR training, and the successfully trained rats were divided into 7 groups: blank group, zicronapine20, 40 and 60 mg/kg groups, risperidone 0.2, 0.4 and 0.8 mg/kg groups, with 5 to 6 rats in each group. The effects of zicronapine on avoidance response times of rats were investigated. (5)Seventy ICR mice were divided into blank group (Veh+NS), model group (Veh+PCP) and risperidone 0.05 mg/kg+PCP group. The effects of zicronapine (0.5, 1.0, 2.0 mg/kg)+PCP groups on novel object recognition disorder in mice were investigated. (6) The affinity of zicronapine to D 1, D 2, 5-HT 2A, 5-HT 6 and 5-HT 2C was investigated by radiolig and receptor binding assay. One-way analysis of variance was used for measurement data, and non-parametric U test was used for count data. Results:(1) Compared with the model group, 3.0 and 10.0 mg/kg of zicronapine significantly inhibited APO-induced climbing behavior in mice ( Z=-3.43, -4.07; P<0.01), and its ED 50 was 4.31 mg/kg. Risperidone at doses of 0.10, 0.30 and 1.00 mg/kg significantly inhibited the climbing behavior of mice ( Z=-1.83, -2.48, -4.26; P<0.05 or P<0.01) and the ED 50 was 0.19 mg/kg. (2) Compared to the model group, zicronapine 3.0 and 10.0 mg/kg significantly inhibited MK-801-induced hyperactivity behavior in mice ( t=-7.18, 3.90; P<0.01), and the ED 50 was 2.63 mg/kg. Risperidone 0.01, 0.03, 0.10 and 0.30 mg/kg significantly inhibited hyperactivity behavior in mice ( t=-3.02, 4.98, -6.08, 7.10; all P<0.01), and the ED 50 was 0.011 mg/kg. (3) The ED 50 of zicronapine and risperidone were 35.36 mg/kg and 1.25 mg/kg, respectively. (4) Both zicronapine and risperidone could inhibit the number of avoidance responses in a dose-dependent manner. Zicronapine dose at 40 and 60 mg/kg significantly inhibited the number of conditioned avoidance responses in rats ( t=11.84, 13.07; P<0.01), and the ED 50 was 34.36 mg/kg. Risperidone of 0.8 mg/kg could significantly inhibit the number of conditioned avoidance responses in rats ( t=13.50, P<0.01), and the ED 50 was 0.60 mg/kg. (5) Compared to the model group, zicronapine 0.5 and 1.0 mg/kg could significantly improve the discrimination index of PCP-induced new object recognition disorder model mice ( t=-3.67, -2.12; P<0.05 and P<0.01) to improve cognitive ability. However, risperidone 0.05 mg/kg had no significant effect on the discrimination index of PCP-induced new object recognition disorder model mice. (6) Zilonapine had high affinity for D 1 (K i=3.21 nmol/L) and 5-HT 2A (K i=13.11 nmol/L) receptors, but weak affinity for D 2 (K i=563.20 nmol/L) receptors. In addition, chilonapine also had high affinity for 5-HT 6 (K i=21.49 nmol/L) and 5-HT 2C (K i=48.90 nmol/L). Risperidone had high affinity for 5-HT 2A , 5-HT 2C and D 2 receptors with K i of 2.37, 18.79 and 4.82 nmol/L, respectively. Risperidone had weak affinity for D 1 and 5-HT6 receptors. Conclusions:Zicronapine has good efficacy in multiple animal models with positive symptoms of schizophrenia and can improve the cognition of mice. Its in vivo efficacy may be related to dopamine D 1 and D 2 receptors and 5-HT 2A and 5-HT 6 receptors.