The Dopamine Pathway

Molecular mechanisms of addiction · First-year biology

One pathway, six ways in

Every addictive drug raises dopamine in the nucleus accumbens. They do it by breaking into different stretches of the same pathway. Watch where each one gets in.

A common misconception. Dopamine molecules do not travel from start to finish. What travels is an electrical signal, an action potential, along the axon. Dopamine waits at the far end, packed in vesicles, and is released only when the signal arrives.
讲解提示开场先纠正一个常见误解：多巴胺分子并不从起点走到终点。沿着轴突 (axon) 跑过去的是电信号，叫动作电位 (action potential)；多巴胺一直装在终点的囊泡 (vesicle) 里，电信号一到才被释放。可以这样说："What travels is electricity. Dopamine waits at the finish line."

The route: five stations

The pink tube is the mesolimbic pathway, drawn inside a real 3D brain. Click a station to see which cases break in there. Drag to rotate, right-drag or Shift-drag to pan, Ctrl + scroll to zoom.

Yellow pulses: action potentials traveling to the finish

    Six cases, side by side

    All six panels show the same circuit from the same angle, at the same moment. Only one thing differs in each. Rotate one and they all rotate. Click ⤢ to enlarge a panel and see every part labeled.

    Action potential Brake signal (GABA) Dopamine Vesicles DAT (vacuum) D1/D2 receptors Drug molecules: the color of each case

    Time is slowed about 4 times. The axon terminal is magnified and the axon is shortened. Dopamine levels come from a simple teaching model; the order (amphetamine-type stimulants highest, then cocaine, then nicotine and opioids) follows rat microdialysis studies (Di Chiara and Imperato 1988). "Firing" and "Brake" show each neuron's rate as a percentage of the no-drug panel.

    讲解提示推荐顺序：先看左上角"No drug"对照组，指出刹车（蓝色脉冲）和吸尘器（青色 DAT）；然后看第一行的尼古丁和阿片类，都作用在起点 ①，一个踩油门，一个松刹车；再看赌博，同样在 ①，但没有任何外来分子；最后看第二行的可卡因和冰毒，它们不改变放电，而是改变终点的回收。可以打开顶部的 Quiz 让学生先猜。

    Takeaways

    Same finish line

    Every case ends the same way: more dopamine reaching receptors in the nucleus accumbens. Drugs that do not do this rarely cause addiction (Nestler 2025).

    Two kinds of doors

    Station 1 cases (nicotine, opioids, gambling) change how often the dopamine neuron fires. Station 3 and 4 cases (cocaine, methamphetamine) change how long dopamine stays in the synapse, however often the neuron fires (Lüscher and Ungless 2006).

    The long-term change is at the finish

    With repeated use, station 5 changes: fewer D2 receptors, and ΔFosB builds up and switches genes for weeks. This is part of why tolerance and craving outlast the drug.

    Treatments use the same doors

    Naloxone pushes opioids off μ-opioid receptors; varenicline partly occupies nicotinic receptors. "Virtually all available treatments for drug addiction act on the initial protein targets" (Nestler and Lüscher 2019).

    Think it through. A medicine called tetrabenazine blocks VMAT2 and nothing else. Would dopamine in the synapse go up or down? Use the stations to explain.
    讲解提示答案：会下降。VMAT2 被堵住，多巴胺装不进囊泡（第 ③ 站），电信号到达时就没有多巴胺可以释放。丁苯那嗪 (tetrabenazine) 正是用这个原理治疗亨廷顿病的不自主运动。这道题检验学生是否理解"每一站各管什么"。

    Sources

    1. Lüscher C, Ungless MA (2006). The mechanistic classification of addictive drugs. PLoS Medicine 3: e437. Link ↗
    2. Nestler EJ (2025). The biology of addiction. Science Signaling 18: eadq0031 (table 1 lists each drug's protein target). Link ↗
    3. Nestler EJ, Lüscher C (2019). The molecular basis of drug addiction: linking epigenetic to synaptic and circuit mechanisms. Neuron 102: 48–59. Link ↗
    4. Liu X, Wang F, Le Q, Ma L (2023). Cellular and molecular basis of drug addiction: the role of neuronal ensembles in addiction. Current Opinion in Neurobiology 83: 102813. Link ↗
    5. Johnson SW, North RA (1992). Opioids excite dopamine neurons by hyperpolarization of local interneurons. Journal of Neuroscience 12: 483–488. PubMed ↗
    6. Mansvelder HD, McGehee DS (2002). Cellular and synaptic mechanisms of nicotine addiction. Journal of Neurobiology 53: 606–617. PubMed ↗
    7. Sulzer D, Sonders MS, Poulsen NW, Galli A (2005). Mechanisms of neurotransmitter release by amphetamines: a review. Progress in Neurobiology 75: 406–433. PubMed ↗
    8. Di Chiara G, Imperato A (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. PNAS 85: 5274–5278. Link ↗
    9. Fiorillo CD, Tobler PN, Schultz W (2003). Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299: 1898–1902. Link ↗
    10. U.S. Department of Health and Human Services (2016). Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health, chapter 2. Link ↗
    11. Brain anatomy: BodyParts3D, © The Database Center for Life Science, licensed under CC Attribution 4.0 International.