Molecular mechanisms of the methylphenidate-induced psychostimulus effects

甲基苯丙胺是一种强烈的成瘾性精神兴奋剂，对哺乳动物的中枢神经系统有很大的影响。已知哌醋甲酯具有类似于甲基苯丙胺的精神刺激作用，通常用于治疗发作性睡病和严重抑郁症以及患有注意力缺陷/多动症的儿童和青少年。在本研究中，我调查了滥用潜力的哌醋甲酯相比，甲基苯丙胺。皮下注射甲基苯丙胺或哌醋甲酯可增加小鼠延髓核细胞外多巴胺水平。甲基苯丙胺或哌醋甲酯对多巴胺释放的刺激被抑制，预处理与选择性磷脂酰肌醇3-激酶（PI 3-K）抑制剂渥曼青霉素的核内注射。有趣的是，甲基苯丙胺，而不是哌甲酯，也增加了细胞外5-HT水平在这方面。此外，重复治疗甲基苯丙胺加剧了过敏的发展hypermotortion，而哌醋甲酯未能诱导行为敏化。此外，在体外处理甲基苯丙胺引起了一个持久的星形胶质细胞激活在边缘神经元/胶质细胞共培养，但哌醋甲酯未能引起这样的效果。这些结果表明，与甲基苯丙胺，哌醋甲酯显示缺乏发展的行为敏化其hypermotorism和诱导可逆的星形胶质细胞激活。此外，甲基苯丙胺的5-HT释放的增强可能，至少部分地，有助于甲基苯丙胺治疗后的行为敏化和星形胶质细胞功能的不可逆变化的发展。

Methamphetamine is a powerfully addictive psychostimulant that dramatically affects the mammalian central nervous system. Methylphenidate, which has been known to have psychostimulus effects similar to methamphetamine, is commonly used in the treatment of narcolepsy and serious depression and with children and adolescents who have attention deficit/hyperactivity disorder. In the present study, I investigated the abuse potentiality of methylphenidate, compared to that of methamphetamine. The subcutaneous administration of either methamphetamine or methylphenidate increased the extracellular dopamine levels in the nucleus accumbens of mice. The stimulation of dopamine release by methamphetamine or methylphenidate was suppressed by pretreatment with an intra-nucleus accumbens injection of a selective phosphoinositide 3-kinase (PI3-K) inhibitor wortmannin. Interestingly, methamphetamine, but not methylphenidate, also increased the extracellular 5-HT levels in this area. Furthermore, repeated treatment with methamphetamine aggravated the development of sensitization to hyperlocomotion, whereas methylphenidate failed to induce behavioral sensitization. Moreover, in vitro treatment with methamphetamine caused a long-lasting astrocytic activation in limbic neuron/glia cocultures, but methylphenidate failed to cause such an effect.These findings suggest that unlike methamphetamine, methylphenidate shows a lack of the development of behavioral sensitization to its hyperlocomotion and induces the reversible astrocytic activation. Furthermore, the enhancement of 5-HT release by methamphetamine may, at least in part, contribute to the development of behavioral sensitization and irreversible changes in astrocytic function after methamphetamine treatment.