Margolis Elyssa B, Lock Hagar, Chefer Vladimir I, Shippenberg Toni S, Hjelmstad Gregory O, Fields Howard L
Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA 94608, USA.
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2938-42. doi: 10.1073/pnas.0511159103. Epub 2006 Feb 13.
Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. Kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.
源自腹侧被盖区（VTA）的多巴胺能传入神经是介导唤醒、动机和强化的神经回路中的关键要素。这些传入神经的两个主要靶点是内侧前额叶皮质（mPFC）和伏隔核（NAc）。虽然mPFC中的多巴胺（DA）与工作记忆和注意力过程有关，但NAc中的DA是对奖励预测线索做出反应所必需的。这些不同的功能表明投射到这些脑区的多巴胺能神经元具有独立的放电模式。事实上，mPFC和NAc中的DA释放可以受到不同的调节。然而，迄今为止，电生理研究在很大程度上忽略了VTA神经元之间的异质性。在这里，我们提供了基于投射靶点对DA神经活动和相应DA释放进行不同神经递质控制的直接证据。κ阿片受体激动剂抑制投射到mPFC的VTA DA神经元，但不抑制投射到NAc的神经元。此外，在向VTA局部注入κ阿片受体激动剂后，mPFC中的DA水平降低，但NAc中的DA水平未降低。这些发现表明，特定脑区的DA释放可以通过对VTA DA神经元亚群的阿片类药物靶向进行独立调节。对投射到mPFC的VTA DA神经元的选择性控制对于理解成瘾、注意力障碍和精神分裂症具有重要意义，所有这些都与mPFC中的DA功能障碍有关。
