Cocaine-induced potentiation of synaptic strength in dopamine neurons: Behavioral correlates in GluRA(-/-) mice
Cocaine-induced potentiation of synaptic strength in dopamine neurons: Behavioral correlates in GluRA(-/-) mice
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DOI：
10.1073/pnas.0401553101
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发表时间：
2004-09-28
影响因子：
11.1
通讯作者：
Malenka, RC
中科院分区：
文献类型：
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作者：
Dong, Y;Saal, D;Malenka, RC
中脑边缘多巴胺（DA）系统中的突触可塑性被认为有助于介导行为敏化的神经适应，这是成瘾核心方面的模型。最近，它已被证明，滥用药物的多种类别，以及急性应激，增强强度在兴奋性突触中脑DA神经元。在这里，我们表明，可卡因和应激诱导的突触增强涉及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的上调。这种增强需要α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体亚基GluRA，这一点在缺乏该亚基的小鼠中的缺失得到了证明。可卡因引起的，但不是应力引起的，DA神经元的突触增强被D1样受体拮抗剂阻断，表明这些形式的经验依赖性突触修饰的体内触发机制不同。令人惊讶的是，可卡因的行为敏化引起的GluRA（-/-）小鼠，表明DA神经元兴奋性突触传递的增强是不必要的这种形式的行为可塑性。然而，GluRA（-/-）小鼠并没有表现出条件性运动反应时，放置在一个背景下，先前与可卡因配对，他们也没有表现出条件性位置偏好可卡因。我们认为，药物诱导的增强兴奋性突触传递中脑DA神经元，虽然不需要行为敏化本身，可能有助于归因于药物相关线索的激励价值。
Synaptic plasticity in the mesolimbic dopamine (DA) system is thought to contribute to the neural adaptations that mediate behavioral sensitization, a model for core aspects of addiction. Recently, it has been demonstrated that multiple classes of drugs of abuse, as well as acute stress, enhance strength at excitatory synapses on midbrain DA neurons. Here, we show that both the cocaine- and stress-induced synaptic enhancement involves an up-regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This enhancement requires the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluRA as evidenced by its absence in mice lacking this subunit. The cocaine-elicited, but not the stress-elicited, synaptic potentiation in DA neurons was blocked by a D1-like receptor antagonist, indicating that the in vivo triggering mechanisms differ for these forms of experience-dependent synaptic modification. Surprisingly, behavioral sensitization to cocaine was elicited in GluRA(-/-) mice, indicating that potentiation of excitatory synaptic transmission in DA neurons is not necessary for this form of behavioral plasticity. However, GluRA(-/-) mice did not exhibit a conditioned locomotor response when placed in a context previously paired with cocaine, nor did they exhibit conditioned place preference in response to cocaine. We suggest that the drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.