Konradi C, Cole R L, Heckers S, Hyman S E
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown 02129.
J Neurosci. 1994 Sep;14(9):5623-34. doi: 10.1523/JNEUROSCI.14-09-05623.1994.
Amphetamine is a psychostimulant drug of abuse that can produce long-lived changes in behavior including sensitization and dependence. The neural substrates of these drug effects remain unknown, but based on their prolonged time course, we hypothesize that they involve drug-induced alterations in gene expression. It has recently been demonstrated that amphetamine regulates the expression of several genes, including c-fos, via dopamine D1 receptors in rat striatum. Here we report that amphetamine induces phosphorylation of transcription factor cAMP response element binding protein (CREB) in rat striatum in vivo and that dopamine D1 receptor stimulation induces phosphorylation of CREB within specific complexes bound to cAMP regulatory elements. In addition, we show by antisense injection that CREB is necessary for c-fos induction by amphetamine in vivo. Since CREB has been implicated in the activation of a number of immediate-early genes as well as several neuropeptide genes, CREB phosphorylation may be an important early nuclear event mediating long-term consequences of amphetamine administration.
苯丙胺是一种滥用的精神兴奋剂药物，可产生包括敏感化和依赖性在内的行为长期变化。这些药物作用的神经基质尚不清楚，但基于其较长的时间进程，我们推测它们涉及药物诱导的基因表达改变。最近有研究表明，苯丙胺通过大鼠纹状体中的多巴胺D1受体调节包括c-fos在内的多个基因的表达。在此我们报告，苯丙胺在体内可诱导大鼠纹状体中转录因子环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化，并且多巴胺D1受体刺激可在与环磷酸腺苷调节元件结合的特定复合物内诱导CREB的磷酸化。此外，我们通过反义注射表明，CREB对于苯丙胺在体内诱导c-fos是必需的。由于CREB已被认为与许多即早基因以及几种神经肽基因的激活有关，因此CREB磷酸化可能是介导苯丙胺给药长期后果的重要早期核事件。
