Role of Frontal Cortex in the Development of Methamphetamine-induced Reverse Tolerance

小剂量舒必利是一种选择性的D_2受体阻滞剂，被认为优先阻断DA自身受体。但我们之前的实验并没有提供支持这一假设的结果。实验结果表明，小剂量舒必利优先阻断额叶皮质DA神经传递。结果表明，小剂量舒必利可逆转甲基苯丙胺诱导的单侧额叶皮质消融大鼠的对侧旋转，提示其优先阻断额叶DA神经传递。但在体内脑透析法实验中，低剂量舒必利与高剂量舒必利相比，增加细胞外DA含量的幅度相同，但速度较慢。因此，小剂量舒必利优先阻断DA自身受体的可能性是不可否认的。我们的结果表明，小剂量舒必利优先阻断额叶皮质DA传递和/或DA自身受体。甲基苯丙胺诱导的逆转耐受的神经化学基础被认为是DA自身受体亚敏感和额叶DA神经传递功能减退。这些亚敏感和功能减退是甲基苯丙胺反复刺激DA的结果。因此，阻断额叶DA神经递质和DA自身受体可能抑制了反向耐受的形成。在目前的主要实验中，小剂量舒必利治疗优于每一次甲基苯丙胺治疗。但是，与重复注射甲基苯丙胺的大鼠相比，这种联合药物治疗的大鼠表现出相同程度的可逆耐受性。这一结果表明，另一种生化机制参与了逆耐受的形成。

Low dose of sulpiride, which is a selective D_2-receptor blocker, is thought to block DA autoreceptor preferencially. But our previous experiments did not provide the findings supporting this hypothesis. Results of our experiments showed that low dose of sulpiride preferencially blocked DA neurotransmission in frontal cortex. Present result, which shows that low dose of sulpiride reverses methamphetamine-induced contralateral rotation of unilateral frontal cortex ablation rats, indicates its preferencial blockade of frontal DA neurotransmission. But, in the experiment used with in vivo brain dialysis method, low dose sulpiride increases extracellular DA content in same extent but more slowly compared with high dose sulpiride. Accordingly the possibility that low dose sulpiride blocks preferencially DA autoreceptor is undeniable from this result. Our present results indicates that low dose sulpiride preferencially blocks frontal cortex DA transmission and/or DA autoreceptor.Neurochemical basis of methamphetamine-induced reverse tolerance is thought to be manifestation of subsensitivity of DA autoreceptor and hypofunction of frontal DA neurotransmission. these subsensitivity and hypofunction are result of repeate DA stimulation by methamphetamine treatment. Therefor, the blockade of Frontal DA neurotransmission and DA autoreceptor might inhibit the development of reverse tolerance. In present main experiment, low dose sulpiride treatment ptrecedes each methamphetamine treatment. But rats with this combination drug treatment exhibit reverse tolerance in same degre with rats injected with repeated methamphetamine alone. This result indicates that another biochemical mechanism implicated in the development of reverse tolerance.