左旋四氢巴马汀对精神兴奋剂诱导的小鼠高活动性和行为敏化的影响

目的研究左旋四氢巴马汀(l-THP)对可卡因及甲基苯丙胺(去氧麻黄碱)所致小鼠高活动性和行为敏化的影响。方法采用自发活动实验检测小鼠的运动距离,研究l-THP对小鼠基础活动性及对可卡因或甲基苯丙胺诱发的小鼠高活动性的影响。采用反复间断给药方式建立行为敏化模型,分别在行为敏化的形成期和激发前进行干预,并检测小鼠的运动距离,研究l-THP对可卡因或甲基苯丙胺诱发的小鼠行为敏化形成和表达的影响。结果①与正常对照组相比,l-THP在5 mg/kg(ig)剂量下小鼠的运动距离无显著差异,10 mg/kg组的运动距离为(26.7±14.8)m,显著低于正常对照组(70.3±34.7)m(P<0.01);②给予l-THP(5、10 mg/kg,ig)后给予可卡因(10 mg/kg,ip),小鼠的运动距离分别为(161.6±42.0)m、(118.0±70.1)m,显著低于可卡因模型组(254.0±58.6)m(P<0.01);给予l-THP(5、10 mg/kg,ig)后给予甲基苯丙胺(1 mg/kg,ip),小鼠的运动距离分别为(212.0±79.1)m、(124.4±48.7)m,显著低于甲基苯丙胺模型组(354.2±210.2)m(P<0.05、P<0.01);③在行为敏化形成期连续7 d伴随可卡因(20 mg/kg,ip)给予l-THP(10 mg/kg,ip),显著抑制可卡因诱发的小鼠行为敏化的形成及戒断后的激发(P<0.05),l-THP(2.5、5 mg/kg,ig)有降低敏化形成程度及戒断后激发的趋势;在形成期连续8 d伴随甲基苯丙胺(1 mg/kg,ip)给予l-THP(2.5、5、10 mg/kg,ig)有降低甲基苯丙胺诱发小鼠行为敏化形成及戒断后激发的趋势;④行为敏化激发前单次给予l-THP(2.5、5、10 mg/kg,ig)可剂量依赖地抑制可卡因或甲基苯丙胺诱发的小鼠行为敏化的表达,给予l-THP 5、10 mg/kg后给予可卡因(10 mg/kg,ip)进行激发,小鼠的运动距离分别为(222.9±112.6)m和(173.0±73.8)m,显著低于可卡因模型组小鼠的运动距离(368.6±59.4)m(P<0.01);给予l-THP 5、10 mg/kg后给予甲基苯丙胺(0.5 mg/kg,ip)进行激发,小鼠的运动距离分别为(227.3±58.9)m和(138.0±50.6)m,显著低于甲基苯丙胺模型组(408.6±128.6)m(P<0.01)。结论 l-THP在不产生镇静作用的剂量下能抑制可卡因或甲基苯丙胺诱发的小鼠高活动性和行为敏化的表达,并具有降低行为敏化形成的趋势,提示l-THP具有减轻精神兴奋剂成瘾的形成、预防复吸的作用。

Effect of levo-tetrahydropalmatine on psychostimulants-induced hyperactivity and behavioral sensitization in mice

Objective To investigate the effect of levo-tetrahydropalmatine(l-THP)on the cocaine-or methamphetamine(metamfetamine,MA)-induced hyperactivity and behavioral sensitization in mice. Methods The locomotion test was used to evaluate the effect of l-THP on the basal locomotion and the cocaine-or methamphetamine-induced hyperactivity by testing the locomotion distance in mice. The behavioral sensitization model was established by repeated and intermittent administration of drugs,interventions were carried out during the development phase or before challenge,and the locomotion distance was tested so as to evaluate the effect of l-THP on the development and the expression of cocaine-or methamphetamine-induced behavioral sensitization,respectively.Results ① Compared with control group,l-THP 5 mg/kg failed to significantly affect the basal locomotion distance in mice,while the locomotion distance(26.7±14.8)m in the l-THP(10 mg/kg,ig)group was significantly lower than that in the control group(70.3±34.7)m(P<0.01).② The locomotion distance in the groups of l-THP(5 and 10 mg/kg,ig)followed by cocaine(10 mg/kg,ip)were(161.6±42.0)m and(118.0±70.1)m,respectively,which were significantly lower than that in the cocaine group(254.0±58.6)m(P<0.01),while the locomotion distance in the group of l-THP(5 and 10 mg/kg,ig)followed by methamphetamine(1 mg/kg,ip)were(212.0±79.1)m and(124.4±48.7)m,respectively,which were significantly lower than that in the methamphetamine group(354.2±210.2)m(P<0.05,P<0.01).③ Daily administration of l-THP 10 mg/kg(ig)prior to cocaine for continuous 7 days significantly attenuated the development of cocaine(20 mg/kg,ip)-induced behavioral sensitization(P<0.05)and the challenge after abstinence in mice,while l-THP at the dosage of 2.5 and 5 mg/kg(ig)showed the tendency to reduce the development of cocaine-induced behavioral sensitization and the challenge after abstinence. Meanwhile,administration of l-THP(2.5,5,10 mg/kg,ig)along with methamphetamine(1 mg/kg,ip)for 8 days also showed a tendency to reduce the development of methamphetamine-induced behavioral sensitization.④ Acute treatment with l-THP(2.5,5,10 mg/kg)on the challenge day reduced the expression of cocaine-or methamphetamine-induced behavioral sensitization in a dose-dependent manner in mice. The locomotion distances in the groups of l-THP 5 and 10 mg/kg(ig)followed by cocaine(10 mg/kg,ip)were(222.9±112.6)m and(173.0±73.8)m,respectively,significantly lower than that in the cocaine group(368.6±59.4)m(P<0.01),while the locomotion distance in the groups of l-THP 5 and 10 mg/kg(ig)followed by methamphetamine(0.5 mg/kg,ip)were(227.3±58.9)m and(138.0±50.6)m,respectively,significantly lower than that in the methamphetamine group(408.6±128.6)m(P<0.01). Conclusion l-THP inhibited the hyperactivity and the expression of behavioral sensitization induced by cocaine or methamphetamine,and showed the tendency to reduce the development of behavioral sensitization with no sedative effects in mice,suggesting that l-THP has the potential to attenuate the development of psychostimulants addiction and prevent the relapse.