Salomon Lucas, Lanteri Christophe, Godeheu Gérard, Blanc Gérard, Gingrich Jay, Tassin Jean-Pol
CNRS UMR 7148, Collège de France, 11, Place Marcelin Berthelot, 75231, Paris Cedex 05, France.
Psychopharmacology (Berl). 2007 Sep;194(1):11-20. doi: 10.1007/s00213-007-0810-3. Epub 2007 May 19.
Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either alpha1b-adrenergic or 5-HT2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking alpha1b-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.
To explore why there is a discrepancy between pharmacological and genetic 5-HT2A receptor blockade.
Locomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, alpha1b-adrenergic, and 5-HT2A receptor antagonists, respectively.
Repeating 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.
Because 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.
尽管对右旋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受体几乎完全抑制了小鼠对右旋苯丙胺诱导的运动反应。与这一发现一致，缺乏α1b - 肾上腺素能受体的小鼠对右旋苯丙胺几乎没有反应。然而，我们在此表明，矛盾的是，缺乏5 - HT2A受体（5 - HT2A - R KO）的小鼠对右旋苯丙胺的运动反应比野生型（WT）同窝小鼠高出两倍。
探讨药理学和基因敲除5 - HT2A受体之间存在差异的原因。
分别在哌唑嗪和/或SR46349B（α1b - 肾上腺素能和5 - HT2A受体拮抗剂）存在的情况下，测量对右旋苯丙胺的运动反应和行为敏化。
重复注射苯丙胺仍会增加5 - HT2A - R KO小鼠对右旋苯丙胺的运动反应，其水平与致敏的WT小鼠相似。正如预期的那样，SR46349B（1毫克/千克）对5 - HT2A - R KO小鼠没有影响。每千克1毫克的哌唑嗪完全阻断了5 - HT2A - R KO未致敏动物对右旋苯丙胺诱导的运动反应，但在致敏的5 - HT2A - R KO小鼠中需要3毫克/千克。
由于未致敏的5 - HT2A - R KO小鼠对右旋苯丙胺表现出增强的皮质去甲肾上腺素能反应，我们的数据表明，重复给予右旋苯丙胺会改变5 - HT2A - R KO小鼠中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。致敏的WT小鼠中SR46349B效率的显著降低表明，在致敏过程中5 - HT受体对去甲肾上腺素能传递的调节作用受到破坏，因此代表了对右旋苯丙胺行为致敏的生理基础。
