Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.
PLoS One. 2010 Dec 31;5(12):e15870. doi: 10.1371/journal.pone.0015870.
Addictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.
METHODOLOGY/PRINCIPAL FINDINGS: We used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT) is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.
CONCLUSIONS/SIGNIFICANCE: We propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.
成瘾药物的共同之处在于，它们会导致中脑边缘奖励系统中的多巴胺（DA）浓度激增，并在腹侧被盖区（VTA）的 DA 神经元中引发突触可塑性。例如，可卡因会促使谷氨酸能突触中的 GluA2 缺失型 AMPAR（AMPAR）插入 DA 神经元。然而，可卡因驱动这种 AMPAR 重分布的分子靶标仍不清楚，其他成瘾药物（吗啡和尼古丁）是否通过其对中脑边缘 DA 系统的影响导致类似的变化。
方法/主要发现：我们使用野生型和转基因小鼠的体外电生理技术观察成瘾药物对 DA 神经元兴奋性输入的调制。为了观察 AMPAR 重分布，我们将 GluA2 AMPAR 亚基的后嵌入免疫组织化学与电子显微镜结合使用。我们还使用表达通道视紫红质的双 floxed AAV 病毒与 DAT Cre 小鼠系一起使用，以选择性地在 VTA DA 神经元中表达 ChR2。我们发现，在可卡因对多巴胺转运蛋白（DAT）的作用被特异性阻断的小鼠中，药物给药后 AMPAR 重分布不存在。此外，已知增加多巴胺水平的成瘾药物会导致类似的 AMPAR 重分布。最后，光遗传学激活 DA VTA 神经元足以驱动 GluA2 缺失型 AMPAR 的插入，模拟单次注射吗啡、尼古丁或可卡因后观察到的变化。
结论/意义：我们提出中脑边缘多巴胺系统是成瘾药物可以改变神经回路的一个汇聚点。我们还表明，直接激活 DA 神经元足以驱动 AMPAR 重分布，这可能是与非物质相关成瘾的早期步骤相关的机制。
