The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior
The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior
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DOI：
10.1038/npp.2013.106
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发表时间：
2013-09-01
影响因子：
7.6
通讯作者：
Spanagel, Rainer
中科院分区：
文献类型：
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作者：
Cannella, Nazzareno;Halbout, Briac;Spanagel, Rainer
为可卡因成瘾患者开发药物是困难的，许多有希望的临床前候选药物在临床试验中失败了。将临床前的发现转化为人类情况很困难的一个原因是，药物测试通常是在动物没有表现出成瘾特征的行为程序中进行的。最近，一种基于DSM-IV的动物模型已经被开发出来，它可以研究向成瘾行为的转变。突触可塑性的改变参与了向可卡因成瘾的转变。特别是，已有研究表明，代谢性谷氨酸受体2/3(mGluR2/3)介导的长期抑郁在成瘾样大鼠的前脑皮质中受到抑制。因此，我们假设成瘾大鼠在寻找可卡因时可以使用mGluR2/3激动剂进行治疗。事实上，用mGluR2/3激动剂LY379268(0、0.3和3 mg/kg)系统治疗成瘾大鼠后，线索诱导的可卡因寻找恢复明显减少。为了分析mGluR2和mGluR3在线索诱导的恢复中所起的作用，我们分析了几个相关脑区的mRNA表达模式，但没有发现类可卡因成瘾和非成瘾大鼠之间的任何显著差异，表明观察到的行为差异是由于翻译调控而不是转录调控。研究mGluR2和mGluR3在调节成瘾性行为中的作用的另一种可能性是使用基因敲除模型。由于mGluR2基因敲除由于运动障碍而不能用于手术中，我们只测试了mGluR3基因敲除。在恢复方面，这些小鼠与对照组没有不同，这表明mGluR2受体在调节成瘾性行为方面起着关键作用。
Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.