多巴胺D3受体拮抗剂YQA14对甲基苯丙胺所致小鼠社交识别和新奇物体识别能力损伤的影响

Effects of dopamine D3 receptor antagonist YQA14 on methamphetamine-induced impairments of the novel object recognition ability and the social recognition ability in mice

目的研究高选择性多巴胺D3受体阻断剂YQA14对甲基苯丙胺(methamphetamine)造成的小鼠社交识别和新奇物体识别能力损伤的影响。方法 1.将C57BL/6J雄性小鼠分为模型组、YQA14(12.5和25 mg/kg)治疗组,先对未经药物处理的小鼠进行社交识别和新奇物体识别基础能力测试,其后甲基苯丙胺腹腔注射(ip),每日1次,连续给药10 d后,各组分别单次给予溶剂或不同剂量YQA14(12.5和25 mg/kg,ip),末次给药后观察甲基苯丙胺对小鼠认知功能的损伤,以及YQA14对小鼠认知功能损伤的影响。2.将C57BL/6J雄性小鼠分为模型组、YQA14(6.25、12.5和25 mg/kg)治疗组,先对未经药物处理的小鼠进行社交识别和新奇物体识别基础能力测试,其后隔日给予1次甲基苯丙胺(ip),共4次,且每次甲基苯丙胺处理前20 min各组分别给予1次溶剂或YQA14(6.25、12.5和25 mg/kg,ip),连续4个周期(8 d)后,再单次给予溶剂或不同剂量YQA14(6.25、12.5和25 mg/kg,ip),末次给药后观察甲基苯丙胺对小鼠认知功能的损伤,以及YQA14对认知功能损伤的影响。结果 1.与造模前相比,连续给予甲基苯丙胺10 d后,模型组小鼠社交识别指标(T1-T2)和新奇物体识别指数(RI)显著降低(P<0.05);与模型组相比,12.5和25 mg/kg YQA14治疗组小鼠T1-T2和RI值均无显著差异(P>0.05),与造模前相比均显著降低(P<0.05)。2.与造模前相比,隔日给予甲基苯丙胺及YQA14(6.25、12.5和25 mg/kg)4个周期(8 d)后,模型组小鼠T1-T2显著降低(P<0.05),RI值无显著差异(P>0.05);与模型组相比,6.25、12.5和25 mg/kg YQA14治疗组小鼠T1-T2和RI值均无显著性差异(P>0.05),与造模前相比T1-T2值明显降低(P<0.05),RI值无显著差异(P>0.05)。结论甲基苯丙胺能显著损伤小鼠社交识别和新奇物体识别能力,但YQA14不能减轻损伤,提示甲基苯丙胺造成的社交识别和新奇物体识别能力损伤可能不是通过多巴胺D3受体介导的。

Objective To study the effects of the high selective dopamine D3 receptor antagonist YQA14 on methamphetamine-induced impairments of the social recognition ability and the novel object recognition ability in mice. Methods 1. Male C57 BL/6 J mice were divided into control and YQA14（12.5 and 25 mg/kg,ip）groups. The social recognition ability and the novel object recognition ability in untreated mice were tested,then methamphetamine was administered once daily for 10 days,then vehicle or YQA14（12.5 and 25 mg/kg,ip）was administered once to the mice in each group. After the last administration,the methamphetamineinduced cognitive impairments and the effect of YQA14 on the methamphetamine-induced cognitive impairment were examined. 2.Male C57 BL/6 J mice were divided into control and YQA14（6.25,12.5 and 25 mg/kg）groups. The social recognition ability and the novel object recognition ability in untreated mice were tested,then methamphetamine was administered once every other day,coupled with the pre-administration of vehicle or YQA14（6.25,12.5 and 25 mg/kg,ip）20 min of the methamphetamine administration. After4 cycles（8 days）of administration,vehicle or YQA14（6.25,12.5 and 25 mg/kg,ip）was additionally administered once to the mice in the relevant groups. After the last administration of vehicle and YQA14,the methamphetamine-induced cognitive impairments and the effect of YQA14 on the methamphetamine-induced cognitive impairment were examined. Results 1. After 10 days of continuous administration of methamphetamine,the social identification index（T1-T2）and the new object recognition index（RI）of the model group were significantly decreased（P〈0.05）. Compared with the model group,there were no significant difference in T1-T2 and RI values in the 12.5 and 25 mg/kg YQA14 treatment groups（P〈0.05）,which were significantly lower than those before modeling（P〈0.05）. 2. After 4 cycles（ 8 days）of methamphetamine and YQA14（ 6.25,12.5 and 25 mg/kg）treatment,the value of T1-T2 in model group decreased significantly（P〈0.05）but RI values were not significantly different（P〉0.05）. Compared with the model group,there were no significant difference in T1-T2 and RI values in the 6.25,12.5 and 25 mg/kg YQA14 treatment groups（P〉0.05）,and the values of T1-T2 decreased significantly than those before modeling（P〈0.05）,but the RI values were not significantly different（P〈0.05）. Conclusion Methamphetamine significantly impaired the social recognition ability and the novel object recognition ability in mice,and YQA14 could not reduce the impairments,suggesting that the impairments induced by methamphetamine may not be mediated by the dopamine D3 receptor.