Valjent Emmanuel, Aubier Benjamin, Corbillé Anne-Gaëlle, Brami-Cherrier Karen, Caboche Jocelyne, Topilko Piotr, Girault Jean-Antoine, Hervé Denis
Institut National de la Santé et de la Recherche Médicale, Unité 536, F-75005 Paris, France.
J Neurosci. 2006 May 3;26(18):4956-60. doi: 10.1523/JNEUROSCI.4601-05.2006.
The extracellular signal-regulated kinases (ERKs) 1/2 pathway is stimulated by drugs of abuse in striatal neurons through coincident activation of dopamine D1 and glutamate NMDA receptors and is critical for long-lasting behavioral effects of these drugs. Although regulation of transcription is a major target of ERK, the precise mechanisms by which it contributes to behavioral alterations is not known. We examined the role of Zif268, an immediate-early gene induced by drugs of abuse under the control of ERK, in behavioral responses to cocaine using knock-in mutant mice in which Zif268 was replaced by LacZ. No biochemical or behavioral differences between mutant and wild-type mice were observed in basal conditions or in acute responses to cocaine injection. In contrast, locomotor sensitization to single or repeated cocaine injections was dramatically diminished in both heterozygous and homozygous Zif268 mutant mice. Conditioned place preference in response to cocaine was prevented in Zif268-deficient mice. This effect was not attributable to a general learning deficit because the mutant mice displayed normal conditioned place preference when food was used as reward. Our results provide direct genetic evidence for the requirement of Zif268 for long-lasting association of environmental context with specific behavioral responses after short exposures to cocaine. They also underline the common molecular machinery involved in long-lasting drug-induced behavioral alterations and the formation of other types of memory.
细胞外信号调节激酶（ERKs）1/2通路在纹状体神经元中通过多巴胺D1受体和谷氨酸N-甲基-D-天冬氨酸（NMDA）受体的同时激活而被滥用药物所刺激，并且对这些药物的持久行为效应至关重要。尽管转录调节是ERK的主要靶点，但其导致行为改变的确切机制尚不清楚。我们使用Zif268被LacZ取代的敲入突变小鼠，研究了在ERK控制下由滥用药物诱导的即早基因Zif268在对可卡因行为反应中的作用。在基础条件下或对可卡因注射的急性反应中，未观察到突变小鼠和野生型小鼠之间存在生化或行为差异。相比之下，杂合子和纯合子Zif268突变小鼠对单次或重复可卡因注射的运动致敏性均显著降低。Zif268缺陷小鼠对可卡因的条件性位置偏爱被阻止。这种效应并非归因于一般的学习缺陷，因为当使用食物作为奖励时，突变小鼠表现出正常的条件性位置偏爱。我们的结果为Zif268在短期接触可卡因后环境背景与特定行为反应的持久关联中的需求提供了直接的遗传学证据。它们还强调了参与持久药物诱导的行为改变和其他类型记忆形成的共同分子机制。
