Plasticity-Associated Gene Krox24/Zif268 Is Required for Long-Lasting Behavioral Effects of Cocaine
Plasticity-Associated Gene Krox24/Zif268 Is Required for Long-Lasting Behavioral Effects of Cocaine
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DOI：
10.1523/jneurosci.4601-05.2006
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发表时间：
2006-05
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影响因子：
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通讯作者：
E. Valjent;B. Aubier;Anne-Gaëlle Corbillé;K. Brami-Cherrier;J. Caboche;P. Topilko;J. Girault;D. Hervé
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文献类型：
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作者：
E. Valjent;B. Aubier;Anne-Gaëlle Corbillé;K. Brami-Cherrier;J. Caboche;P. Topilko;J. Girault;D. Hervé
细胞外信号调节激酶（ERK）1/2通路通过同时激活多巴胺D1和谷氨酸NMDA受体在纹状体神经元中的滥用药物刺激，并且对于这些药物的长期行为效应至关重要。虽然转录调控是ERK的主要靶点，但其导致行为改变的确切机制尚不清楚。我们研究了Zif 268的作用，即早期基因诱导的药物滥用的ERK控制下，在行为反应可卡因使用敲入突变小鼠，其中Zif 268被替换为LacZ。在基础条件下或可卡因注射的急性反应中，未观察到突变型和野生型小鼠之间的生化或行为差异。与此相反，在杂合和纯合Zif 268突变小鼠中，对单次或重复可卡因注射的运动敏感性显著降低。在Zif 268缺陷小鼠中，对可卡因的条件性位置偏爱被阻止。这种效应并不归因于一般的学习缺陷，因为当食物被用作奖励时，突变小鼠表现出正常的条件性位置偏好。我们的研究结果为Zif 268的需求提供了直接的遗传证据，该需求是在短期暴露于可卡因后，环境背景与特定行为反应的长期关联。他们还强调了持久的药物诱导的行为改变和其他类型的记忆形成所涉及的共同分子机制。
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.