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

舒必利是一种选择性的D_2受体阻滞剂，小剂量被认为可优先阻断DA自身受体。但我们以前的实验没有提供支持这一假设的发现。实验结果表明，低剂量舒必利可优先阻断额叶皮质DA能神经传递。本实验结果表明，低剂量舒必利可逆转甲基苯丙胺诱导的单侧额叶皮层消融大鼠的对侧旋转，表明其对额叶DA神经传递具有优先阻断作用。但在体内脑透析实验中，小剂量舒必利对细胞外DA含量的增加幅度与大剂量舒必利相同，但慢于大剂量舒必利。因此，低剂量舒必利优先阻断DA自身受体的可能性是不可否认的。本研究结果表明，低剂量舒必利优先阻断额叶皮质DA神经传递和（或）DA自身受体，DA自身受体亚敏感性和额叶DA神经传递功能减退是甲基苯丙胺诱导逆转耐受的神经化学基础。这些次敏感性和功能减退是甲基苯丙胺治疗重复DA刺激的结果。因此，阻断额叶DA能神经传递和DA能自身受体可能抑制逆转耐受的形成。在本实验中，小剂量舒必利治疗先于甲基苯丙胺治疗。但这种联合药物治疗的大鼠表现出与单独重复注射甲基苯丙胺的大鼠相同程度的逆转耐受。这一结果表明，另一个生化机制参与了逆转耐受的发展。

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.