McClung Colleen A, Sidiropoulou Kyriaki, Vitaterna Martha, Takahashi Joseph S, White Francis J, Cooper Donald C, Nestler Eric J
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9377-81. doi: 10.1073/pnas.0503584102. Epub 2005 Jun 20.
Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the brain's reward circuit. Mice lacking a functional Clock gene display an increase in cocaine reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward.
尽管昼夜节律与药物成瘾之间存在明确的相互作用，但其相互作用机制仍不清楚。在此，我们确定了Clock基因在调节大脑奖赏回路中的作用。缺乏功能性Clock基因的小鼠对可卡因的奖赏增加，中脑腹侧被盖区（一个关键的脑奖赏区域）多巴胺神经元的兴奋性增强。这些表型与酪氨酸羟化酶（多巴胺合成中的限速酶）的表达增加和磷酸化增加有关，也与已知调节腹侧被盖区多巴胺活性的几个基因的变化有关。这些发现证明了一个与昼夜节律相关的基因Clock参与调节多巴胺功能和可卡因奖赏。
