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J Neuro:新途径揭示大脑对可卡因成瘾机制

来源:生物谷 2012-02-22 12:53

耶鲁大学等处的科学家研究发现,当青少年第一次接触可卡因的时候,大脑就会发射出一种强烈的防御反应,来最大程度的降低药物的效应;近日,来自耶鲁大学研究小组的两项最新研究发现了一个关键基因,该基因可以调节青少年的这种效应,而且可以剧烈干扰这种效应,而且增加小鼠对可卡因的敏感性。

这些新的研究发现可以帮助我们理解,在青少年时候便开始使用可卡因的人为什么药物成瘾和滥用的风险增加的如此明显。这项研究结果将刊登在2月14日和2月21日的国际著名杂志Journal of Neuroscience上。

研究者表示,可卡因的损害性在青年时期尤为高,因为青少年时期,大脑正处于可塑性阶段,向着成年人的大脑转变,耶鲁大学过去的研究表明,第一次接触可卡因时,整联蛋白因子beta1可以进行调节,使得神经元和突触联接容易改变形状,这对于脊椎动物神经系统的发展至关重要。这种结构的改变很有可能是神经系统在第一次遇到可卡因时候的一种自我保护措施,Anthony Koleske教授这样说。

在最新的研究中,耶鲁大学的研究者报道了,他们破坏了该途径(整联蛋白因子beta1调节途径)之后发现,相比正常小鼠,这些受损小鼠需要近乎3倍的可卡因才能刺激机体做出行为的改变。研究揭示,个体的整联蛋白beta1途径的相对强度或许可以解释为什么有些可卡因使用者脱离了那种环境之后,可以戒掉对于药物的成瘾性。

2月14这篇刊登的文章中,研究者是为了寻找一些在防止大脑受可卡因影响和滥用药物中起重要作用的基因,而后期这篇文章是为了描述整联蛋白因子beta1是如何控制突触和突触成熟以及稳定的。(生物谷:T.Shen编译)

Arg Kinase Regulates Prefrontal Dendritic Spine Refinement and Cocaine-Induced Plasticity

Shannon L. Gourley, Anastasia Olevska1, M. Sloan Warren, Jane R. Taylor, and Anthony J. Koleske

Adolescence is characterized by vulnerability to the development of neuropsychiatric disorders including drug addiction, as well as prefrontal cortical refinement that culminates in structural stability in adulthood. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, although intracellular mechanisms are largely unknown. We characterized layer V prefrontal dendritic spine development and refinement in adolescent wild-type mice and mice lacking the cytoskeletal regulatory protein Abl-related gene (Arg) kinase. Relative to hippocampal CA1 pyramidal neurons, which exhibited a nearly linear increase in spine density up to postnatal day 60 (P60), wild-type prefrontal spine density peaked at P31, and then declined by 18% by P56–P60. In contrast, dendritic spines in mice lacking Arg destabilized by P31, leading to a net loss in both structures. Destabilization corresponded temporally to the emergence of exaggerated psychomotor sensitivity to cocaine. Moreover, cocaine reduced dendritic spine density in wild-type orbitofrontal cortex and enlarged remaining spine heads, but arg−/− spines were unresponsive. Local application of Arg or actin polymerization inhibitors exaggerated cocaine sensitization, as did reduced gene dosage of the Arg substrate, p190RhoGAP. Genetic and pharmacological Arg inhibition also retarded instrumental reversal learning and potentiated responding for reward-related cues, providing evidence that Arg regulates both psychomotor sensitization and decision-making processes implicated in addiction. These findings also indicate that structural refinement in the adolescent orbitofrontal cortex mitigates psychostimulant sensitivity and support the emerging perspective that the structural response to cocaine may, at any age, have behaviorally protective consequences.

Integrin β1 Signals through Arg to Regulate Postnatal Dendritic Arborization, Synapse Density, and Behavior

M. Sloan Warren1,2,*, William D. Bradley2,*, Shannon L. Gourley2,5, Yu-Chih Lin2, Mark A. Simpson2, Louis F. Reichardt6, Charles A. Greer1,3,4, Jane R. Taylor1,5, and Anthony J. Koleske1,2,4

Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss, impaired hippocampus-dependent learning, and exaggerated psychomotor sensitivity to cocaine in mice. Our biochemical and genetic experiments demonstrate that the intracellular tail of integrin β1 binds directly to Arg kinase and that this interaction stimulates activity of the Arg substrate p190RhoGAP, an inactivator of the RhoA GTPase. Moreover, genetic manipulations that reduce integrin β1 signaling through Arg recapitulate the integrin β1 knock-out phenotype in a gene dose-sensitive manner. Together, these results describe a novel integrin β1–Arg–p190RhoGAP pathway that regulates dendritic arbor size, promotes synapse maintenance, supports proper hippocampal function, and mitigates the behavioral consequences of cocaine exposure.

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