Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
J Neurosci. 2011 Feb 9;31(6):2180-7. doi: 10.1523/JNEUROSCI.5540-10.2011.
We report here that the Src family tyrosine kinase Lyn negatively regulates the release of dopamine (DA) in the mesolimbic system, as well as the rewarding properties of alcohol. Specifically, we show that RNA interference-mediated knockdown of Lyn expression results in an increase in KCl-induced DA release in DAergic-like SH-SY5Y cells, whereas overexpression of a constitutively active form of Lyn (CA-Lyn) leads to a decrease of DA release. Activation of ventral tegmental area (VTA) DAergic neurons results in DA overflow in the nucleus accumbens (NAc), and we found that the evoked release of DA was higher in the NAc of Lyn knock-out (Lyn KO) mice compared with wild-type littermate (Lyn WT) controls. Acute exposure of rodents to alcohol causes a rapid increase in DA release in the NAc, and we show that overexpression of CA-Lyn in the VTA of mice blocked alcohol-induced (2 g/kg) DA release in the NAc. Increase in DA levels in the NAc is closely associated with reward-related behaviors, and overexpression of CA-Lyn in the VTA of mice led to an attenuation of alcohol reward, measured in a conditioned place preference paradigm. Conversely, alcohol place preference was increased in Lyn KO mice compared with Lyn WT controls. Together, our results suggest a novel role for Lyn kinase in the regulation of DA release in the mesolimbic system, which leads to the control of alcohol reward.
我们在此报告，Src 家族酪氨酸激酶 Lyn 负调控中脑边缘系统多巴胺（DA）的释放，以及酒精的奖赏特性。具体而言，我们表明，通过 RNA 干扰介导的 Lyn 表达敲低导致类似多巴胺能的 SH-SY5Y 细胞中 KCl 诱导的 DA 释放增加，而组成型激活形式的 Lyn（CA-Lyn）的过表达导致 DA 释放减少。腹侧被盖区（VTA）DA 能神经元的激活导致伏隔核（NAc）中的 DA 溢出，我们发现 Lyn 敲除（Lyn KO）小鼠的 NAc 中 DA 的诱发释放比野生型同窝对照（Lyn WT）更高。啮齿动物急性暴露于酒精会导致 NAc 中 DA 释放的快速增加，我们表明，CA-Lyn 在小鼠 VTA 中的过表达阻止了酒精诱导的（2 g/kg）NAc 中 DA 的释放。NAc 中 DA 水平的增加与奖赏相关行为密切相关，CA-Lyn 在小鼠 VTA 中的过表达导致酒精奖赏的减弱，这在条件性位置偏好范式中得到了测量。相反，与 Lyn WT 对照相比，Lyn KO 小鼠的酒精位置偏好增加。总之，我们的研究结果表明 Lyn 激酶在中脑边缘系统 DA 释放的调节中具有新的作用，从而控制了酒精奖赏。
