Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors
Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors
复制标题
缺乏 5-HT2A 受体的小鼠对安非他明的反常本构行为敏感性
DOI：
10.1007/s00213-007-0810-3
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发表时间：
2007
影响因子：
3.4
通讯作者：
J. Tassin
中科院分区：
文献类型：
--
作者：
L. Salomon;C. Lanteri;G. Godeheu;G. Blanc;J. Gingrich;J. Tassin
基本原理虽然对 d-苯丙胺的运动反应被认为是由腹侧纹状体中多巴胺释放增加介导的，但阻断 α1b-肾上腺素能受体或 5-HT2A 受体几乎完全抑制 d-苯丙胺诱导的小鼠运动反应。与这一发现一致的是，缺乏 α1b 肾上腺素受体的小鼠几乎对 d-苯丙胺没有反应。然而，我们在这里发现，矛盾的是，缺乏 5-HT2A 受体 (5-HT2A-R KO) 的小鼠对 d-安非他明的运动反应比野生型 (WT) 同窝小鼠高两倍。目的探讨为什么药理学和遗传 5-HT2A 受体阻断之间存在差异。材料和方法分别存在哌唑嗪和/或SR46349B、α1b-肾上腺素能和5-HT2A受体拮抗剂。结果重复注射安非他明仍然会增加5-HT2A-R KO小鼠对d-安非他明的运动反应，其水平与致敏的WT小鼠相似。正如预期的那样，SR46349B (1 mg/kg) 对 5-HT2A-R KO 小鼠没有影响。每公斤 1 毫克的哌唑嗪可完全阻断 5-HT2A-R KO 幼稚动物中 d-安非他明诱导的运动反应，但对于致敏的 5-HT2A-R KO 小鼠，需要 3 mg/kg。结论由于幼稚 5-HT2A-R KO 小鼠表现出对 d-安非他明的皮质去甲肾上腺素能反应增加，我们的数据表明重复d-amphetamine 改变 5-HT2A-R KO 小鼠的去甲肾上腺素能传递。刺激特定的 5-HT2A 受体会抑制去甲肾上腺素能神经元。致敏WT小鼠中SR46349B效率的显着降低表明5-HT2A受体对去甲肾上腺素能传递的调节作用在致敏过程中发生破坏，因此代表了对d-苯丙胺行为致敏的生理学基础。
RationaleAlthough locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either α1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking α1b-adrenergic receptors hardly respond to d-amphetamine. However, we show here that, paradoxically, mice lacking 5-HT2A receptors (5-HT2A-R KO) exhibit a twofold higher locomotor response to d-amphetamine than wild-type (WT) littermates.ObjectivesTo explore why there is a discrepancy between pharmacological and genetic 5-HT2A receptor blockade.Materials and methodsLocomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, α1b-adrenergic, and 5-HT2A receptor antagonists, respectively.ResultsRepeating amphetamine injections still increases 5-HT2A-R KO mice locomotor response to d-amphetamine at a level similar to that of sensitized WT mice. SR46349B (1 mg/kg) has, as expected, no effect in 5-HT2A-R KO mice. One milligrams per kilogram of prazosin completely blocks d-amphetamine-induced locomotor response in 5-HT2A-R KO naïve animals but 3 mg/kg is necessary in sensitized 5-HT2A-R KO mice.ConclusionsBecause naïve 5-HT2A-R KO mice exhibit an increased cortical noradrenergic response to d-amphetamine, our data suggest that repeated d-amphetamine modifies noradrenergic transmission in 5-HT2A-R KO mice. Stimulation of specific 5-HT2A receptors would inhibit noradrenergic neurons. Dramatic decrease in SR46349B efficiency in sensitized WT mice indicates that a disruption of the regulating role of 5-HT2A receptors on noradrenergic transmission occurs during sensitization and thus represents the physiological basis of behavioral sensitization to d-amphetamine.