A wealth of neuromodulatory transmitters regulate synaptic circuits in the brain. Their mode of signaling, often called volume transmission, differs from classical synaptic transmission in important ways. In synaptic transmission, vesicles rapidly fuse in response to action potentials and release their transmitter content. The transmitters are then sensed by nearby receptors on select target cells with minimal delay. Signal transmission is restricted to synaptic contacts and typically occurs within ~1 ms. Volume transmission doesn’t rely on synaptic contact sites and is the main mode of monoamines and neuropeptides, important neuromodulators in the brain. It is less precise than synaptic transmission, and the underlying molecular mechanisms and spatiotemporal scales are often not well understood. Here, we review literature on mechanisms of volume transmission and raise scientific questions that should be addressed in the years ahead. We define five domains by which volume transmission systems can differ from synaptic transmission and from one another. These domains are (1) innervation patterns and firing properties, (2) transmitter synthesis and loading into different types of vesicles, (3) architecture and distribution of release sites, (4) transmitter diffusion, degradation, and reuptake, and (5) receptor types and their positioning on target cells. We discuss these five domains for dopamine, a well-studied monoamine, and then compare the literature on dopamine with that on norepinephrine and serotonin. We include assessments of neuropeptide signaling and of central acetylcholine transmission. Through this review, we provide a molecular and cellular framework for volume transmission. This mechanistic knowledge is essential to define how neuromodulatory systems control behavior in health and disease and to understand how they are modulated by medical treatments and by drugs of abuse.

大量的神经调节递质调节大脑中的突触回路。它们的信号传导模式通常称为体积传输，与传统的突触传输有重要的不同。在突触传递中，囊泡响应动作电位快速融合并释放其递质内容。然后，选定目标细胞上的附近受体会以最小的延迟感知发射器。信号传输仅限于突触接触，通常发生在约 1 毫秒内。容量传输不依赖于突触接触位点，是单胺和神经肽（大脑中重要的神经调节剂）的主要模式。它不如突触传递精确，并且潜在的分子机制和时空尺度通常没有被很好地理解。在这里，我们回顾了有关体积传输机制的文献，并提出了未来几年应解决的科学问题。我们定义了五个域，通过这些域，体积传输系统可以与突触传输以及彼此之间有所不同。这些领域是 (1) 神经支配模式和发射特性，(2) 递质合成和加载到不同类型的囊泡中，(3) 释放位点的结构和分布，(4) 递质扩散、降解和再摄取，以及 (5)受体类型及其在靶细胞上的定位。我们讨论多巴胺（一种经过充分研究的单胺）的这五个领域，然后将多巴胺的文献与去甲肾上腺素和血清素的文献进行比较。我们包括对神经肽信号传导和中枢乙酰胆碱传输的评估。通过这次审查，我们提供了体积传输的分子和细胞框架。 这种机械知识对于定义神经调节系统如何控制健康和疾病行为以及了解它们如何通过医疗治疗和滥用药物进行调节至关重要。