Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors.
Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors.
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DOI：
10.1016/j.neuron.2008.05.028
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发表时间：
2008-08-14
期刊：
影响因子：
16.2
通讯作者：
Palmiter RD
中科院分区：
文献类型：
--
作者：
Zweifel LS;Argilli E;Bonci A;Palmiter RD
单次暴露于药物滥用产生NMDA受体（NMDAR）依赖性的长时程增强（LTP）的AMPA受体（AMPAR）电流在DA神经元;然而，LTP的药物成瘾的各个方面的重要性还不清楚。为了测试NMDAR依赖性可塑性在成瘾行为中的作用，我们在DA神经元（KO小鼠）中遗传失活了功能性NMDAR信号传导。NMDAR失活导致AMPAR介导的传播增加，这与单一可卡因暴露相关的增加无法区分，但KO小鼠对多种滥用药物的运动反应未发生改变。可卡因的自发致敏的初始阶段是完整的，然而，延迟致敏，发生与长期可卡因戒断没有发生。在KO小鼠中也不存在可卡因测试环境的条件性行为反应。这些发现为NMDAR信号在DA神经元中与药物寻求行为相关的特定行为改变中的作用提供了证据。
A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.
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