Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants
Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants
复制标题
DOI：
10.1523/jneurosci.3936-06.2007
复制
发表时间：
2007-06-27
影响因子：
5.3
通讯作者：
Girault, Jean-Antoine
中科院分区：
文献类型：
--
作者：
Corbille, Anne-Gaelle;Valjent, Emmanuel;Girault, Jean-Antoine
单次服用可卡因或D-安非他明会产生急性运动过度和对后续注射的长期敏感性增加。这种运动敏化揭示了精神兴奋剂诱导大脑可塑性的强大能力，并可能参与成瘾的改变。我们研究了大麻素受体1型（CB 1-R）在单次注射精神兴奋剂的作用。在用CB 1-R反向激动剂N-（哌啶-1-基）-5-（4-碘苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（AM 251）预处理的小鼠中，对可卡因的急性运动反应是正常的，而在一周后的第二次给药中没有观察到敏感性。CB 1-R缺陷小鼠对可卡因和D-苯丙胺的运动反应降低，致敏作用受损。为了确定CB 1-R如何控制精神兴奋剂的长期作用，我们研究了可卡因激活的信号通路。在CB 1-R突变小鼠的纹状体中，辅酶Ⅱ诱导的谷氨酸受体1的cAMP依赖性磷酸化发生了改变，但在AM 251处理的小鼠中没有改变。相反，可卡因诱导的细胞外信号调节激酶（ERK）的磷酸化在CB 1-R突变体和拮抗剂预处理的小鼠中均被阻断。在前脑主神经元或GABA能神经元中条件性缺失CB 1-R可阻止可卡因诱导的背侧纹状体和背侧核ERK激活。我们的研究结果为内源性大麻素系统在调节可卡因持久作用的关键神经元回路中的作用提供了强有力的证据，推测是通过作用于位于纹状体中等多刺神经元末端的CB 1-R。
A single administration of cocaine or D-amphetamine produces acute hyperlocomotion and long-lasting increased sensitivity to subsequent injections. This locomotor sensitization reveals the powerful ability of psychostimulants to induce brain plasticity and may participate in the alterations that underlie addiction. We investigated the role of cannabinoid receptor type 1 (CB1-R) in the effects of a single injection of psychostimulants. The acute locomotor response to cocaine was normal in mice pretreated with the CB1-R inverse agonist N-(piperidin-1-yl)-5-(4- iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole- 3-carboxamide (AM251), whereas no sensitization was observed in response to a second administration a week later. Locomotor responses to cocaine and D- amphetamine were decreased in CB1-R-deficient mice, and sensitization was impaired. To determine how CB1-R controls long- lasting effects of psychostimulants, we studied cocaine-activated signaling pathways. Cocaine- induced cAMP-dependent phosphorylation of glutamate receptor 1 was altered in the striatum of CB1-R mutant mice but not of AM251-treated mice. In contrast, cocaine- induced phosphorylation of extracellular signal- regulated kinase (ERK) was blocked in both CB1-R mutant and antagonist- pretreated mice. Conditional deletion of CB1-R in forebrain principal neurons or GABAergic neurons prevented cocaine-induced ERK activation in dorsal striatum and nucleus accumbens. Our results provide strong evidence for the role of the endocannabinoid system in regulating neuronal circuits critical for long- lasting effects of cocaine, presumably by acting on CB1-R located on terminals of striatal medium spiny neurons.