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.

About this modelshow

Time is slowed about 4 times. The axon terminal is magnified and the axon is shortened. Dopamine levels come from a simple teaching model, tuned so that long-run levels roughly match rat microdialysis studies (Di Chiara and Imperato 1988): amphetamine-type stimulants about 10 times normal, cocaine about 3 times, nicotine and opioids about 1.5 to 2 times. High dopamine also slows the dopamine neuron (D2 autoreceptors); the model shows a mild version, and in some rat studies the slowing is much larger. "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，它们不会让放电变快（多出来的多巴胺反而让放电稍慢），而是改变终点：可卡因堵住回收，冰毒倒空囊泡并让 DAT 反转。可以打开顶部的 Quiz 让学生先猜。

The Dopamine Line: a metro map

The same pathway, drawn like a subway map. Trains are action potentials; passengers are dopamine. Pick a case on the line status board to see where it disrupts service, or click a station on the map. The map runs the same simulation as the 3D view.

Line status

Dopamine on the platform, compared with no drug

How to read this map

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Pink line: the dopamine neuron, from the VTA to the nucleus accumbens
Yellow train: an action potential (the electrical signal)
Pink passengers: dopamine molecules
Depot: vesicles, loaded by VMAT2
Teal loop: recycling by DAT (reuptake)
Blue line and red signal: the GABA brake
Green line: "gas" inputs; nicotine opens its gates
Purple dashed line: inside the receiving neuron, where lasting changes build up

讲解提示比喻对照：列车 = 动作电位 (action potential)；乘客 = 多巴胺 (dopamine)；车库 = 囊泡 (vesicle)，由 VMAT2 装车；站台 = 突触间隙 (synaptic cleft)；青色环线 = DAT 回收 (reuptake)；红色信号灯 = GABA 刹车；⑤ 站的闸机 = D1/D2 受体；紫色虚线 = 受体之后细胞内部的传话链（G 蛋白 → cAMP → ΔFosB）。讲法：先用 No drug 讲清楚"正常运营"，再点状态板上的每种药物，看是哪一站出了故障。站台上的乘客越多，多巴胺越高。可以这样说："Every drug disrupts a different station, but they all crowd the same platform."

The dopamine machine

Pick a case. In the guided story the machine first runs normally while each part is introduced; then the drug arrives and you see exactly which part it tampers with. In “Before & after” the same machine runs twice, side by side: without the drug and with it. Click any part of the story picture to read about it.

▶ Play: Guard the Dopamine Factory a 5-minute game: shield the part of this machine each drug damages

Before: no drug

After

Live readings vs. no drug · they move up and down, like real neurons Rotor speed (firing)100% Brake presses (GABA)100% Dopamine in the gap100%

How to read this picture

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Rotor: the dopamine neuron. It turns on its own; each hammer tap on the contact is one action potential
White glove: glutamate. A hard push makes a burst of taps
Blue operator: a GABA neuron. He steps on the seesaw brake: its red pad presses the hub. Opioids put him to sleep (zZ); alcohol and THC make him drowsy (z)
Sockets on the operator (opioid, alcohol and cannabis cases): his receptors, μ-opioid receptors or CB1 receptors (for alcohol, a stand-in for its many targets). A drug molecule that binds is drawn as a key in a socket; the more keys, the less he brakes
Rockets (nicotine cases): nicotinic receptors on the rotor arms. Nicotine is the key that lights them
Blue-white sparks on the cable: electricity along the axon, not dopamine
Warehouse and factory: one axon terminal; the faint copies are thousands more. The factory makes dopamine; the little gumball machines riding the conveyor belt are vesicles, each refilled through its cyan lid (VMAT2); a pulse opens the gate under the belt and the package over it empties all at once
Gate and teal RECYCLE pumps: release into the gap, and recycling by DAT, which pulls dopamine back to be packed again
Pink marbles: dopamine molecules (not to scale: a real package holds thousands). They spread out at random (they do not fall); some happen to land in receptors, the cups on top of the receiving cells
D1 scale (go): receptor cups on its pan and a heavy weight on the other arm; only many full cups at once sink the pan onto the go pedal
D2 scale (stop): receptor cups on its pan and the stop boot on the other arm; a few full cups keep the boot lifted, a dip lets it stamp. Each scale presses its pedal through a spring; the pedals send signals along the cells’ output fibers (green and red lines) to the BEHAVIOR dial, whose needle swings between DO IT AGAIN, no change and HOLD BACK for the action just taken (for example, the next cigarette)

Pair it with the mouse games

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Two free games from the University of Utah’s Learn.Genetics site zoom in on a single synapse: Mouse Party (seven drugs, a few slides each) and Meth Mouse (methamphetamine only; you run the synapse yourself). Our machine shows the whole pathway, so each mouse fits one part of it.

Mouse	Our case	Part of the machine	Same idea?
Heroin	Opioids	① the brake operator (μ-opioid receptors on GABA neurons)	Yes. Heroin copies the body’s own opioids and switches the brake off (disinhibition).
Marijuana	Cannabis (THC)	① the brake operator (CB1 receptors)	Yes. THC copies the body’s own cannabinoid, anandamide, and loosens the brake.
Cocaine	Cocaine	④ the return pumps (DAT)	Yes. Cocaine blocks the pumps, so dopamine stays in the gap.
Meth, and the Meth Mouse game	Methamphetamine	③ the packages (VMAT2) and ④ the pumps	Yes. Meth enters through the pumps, empties the packages and runs the pumps backward.
Alcohol	Alcohol	① the brake operator, plus a push on the rotor	A different side of the same drug: see the note below.
Ecstasy	none	mostly off this machine	Ecstasy works mainly on serotonin transporters; the game says it adds only a milder dopamine release.
LSD	none	off this machine	LSD acts on serotonin receptors and hardly touches this pathway, one reason it is seldom used compulsively.
No mouse	Nicotine; Gambling & video games	① the rockets on the rotor; the glove and the brake	Not in the mouse games.

Alcohol only looks like a contradiction. Mouse Party says alcohol makes GABA receptors more inhibitory and blocks glutamate receptors: that is why a drinker gets sleepy and forgetful. Our machine says alcohol quiets the GABA brake. Both are true. Alcohol has many targets: across the brain it strengthens inhibition and sedates, while on this pathway it quiets the brake neurons themselves and nudges the dopamine neuron, partly by releasing the body’s own opioids. A looser brake here means more dopamine, the part that makes alcohol rewarding.

Meth Mouse also shows long-term changes. Its receiving cells remove receptors, as in our “Healthy vs addicted” view. Two of its claims go further than the evidence: it says sending cells add more transporters, but brain scans of long-term meth users show fewer DAT, a sign of damaged axon terminals that partly recovers after a year or more without the drug; and it says neurons die, while human studies mainly show damaged terminals.

After Mouse Party, play Guard the Dopamine Factory. Drugs walk in as zombies, each carrying a bomb for every part of this machine it damages; put the right guard in its lane.

讲解提示使用方法：先选"No drug"，让学生跟着字幕看完一遍正常运转（转轮 → 电线 → 仓库和工厂 → 传送带闸门和回收泵 → 两台天平和踏板）；再依次选每种药物：第一次会完整导览，之后每种药物先放 5 秒正常运转回顾，再演示药物到达、哪里被改变、结果，最后是长期变化（一次用药不等于成瘾）。想直接看药物，可以点步骤条上的"2"。点画面上任何一个部件，下面会显示这一站的说明。切换到"Before & after"，左右两台同样的机器同时运转：左边不用药，右边用药，圈出的是药物作用的部位；下方表格汇总所有药物。可以这样说："Same machine every time. Watch which part each drug tampers with."

Opioids up close

Three linked parts of the opioid lesson: the dopamine molecule, the cells and molecules opioids act on, and a driving game.

The real dopamine molecule in 3D: its parts, its size, and how neurons build it from the food we eat.

Five kinds of cells in the reward circuit and the three synapses where opioids act, from cells (µm) down to molecules (nm).

Speed is dopamine and the brakes are GABA cells; an opioid weakens the brakes, so the idling engine pushes the car forward, and it makes the driver drowsy.

Day 0 of 180Health ♥♥♥Score 0

Speed dopamine

SPEED
LIMIT30🏙 City · min 15

Brakes GABA cells100%

Breathing brainstem

Stress alarmCraving pullDrowsyNaloxone kit: 1

Keys: ↑ gas · ↓ brake · ← → steer · N naloxone · P pause · V voice

Presenter notes

比喻对照：车速 = 伏隔核 (nucleus accumbens) 里的多巴胺；发动机 = VTA 的多巴胺神经元；刹车 = VTA 的 GABA 神经元；方向盘/司机 = 前额叶皮层 (PFC)；被拉向药丸的方向盘 = 海马体的用药记忆（渴求 craving）；压力警报 = 杏仁核（戒断时的压力，CRF）；司机的呼吸 = 脑干呼吸中枢 (preBötzinger complex)。

关键机制：① 药丸削弱刹车（VTA GABA 细胞上的 μ 受体，去抑制 disinhibition），平时被刹车按住的怠速发动机（多巴胺神经元自己的基础放电 tonic firing）就自己把车往前推；药丸不踩油门。同时司机犯困（镇静 sedation），转向变慢：真实的阿片中毒是打瞌睡、反应慢，不是兴奋地飙车。注意区分：细胞层面的去抑制（GABA 细胞被安静下来）不等于行为上的“失去自控”。② 呼吸表才是致命的：过量死亡是呼吸停止，不是“开太快”。新手一颗止痛药呼吸约降到 75%，强效药约 40%，含芬太尼的药丸几乎停止，芬太尼再加任何一颗就致命。游戏里呼吸几乎停止时，结局是“有人呼叫 911，司机被送往医院”，不直接写死亡；讲解时可以补充：现实中如果没人救，过量会致命。③ 耐受有两种速度：快感的耐受长得快，呼吸抑制的耐受长得慢 (White & Irvine 1999)，所以“追回原来的快感”越来越危险。④ 戒断：适应后的大脑在没药时刹车“抓得过紧”（cAMP 反弹，GABA 释放增多；Bonci & Williams 1997），刹车表超过 100%，满油门车也被拖住，车速低于正常，压力警报亮。⑤ 治疗站：丁丙诺啡 (buprenorphine)/美沙酮 (methadone) + 心理咨询，渴求降 70%、戒断降 80%，并削弱其他阿片的作用；药物本身是阿片类，治疗期间耐受保持不变。开过下一个蓝色牌子就继续治疗。停止治疗后，药物约 12 天内消退，没有阿片的日子里耐受快速下降，这时复吸 (relapse) 旧剂量最容易过量（Larochelle 2018：只在接受治疗期间死亡率下降，停药后头 4 周风险特别高）。⑥ 纳洛酮 (naloxone) 救命，但会立刻引发戒断；必须由别人给（游戏里是朋友），过量的人自己没法用；它可能比阿片先失效，所以要打 911 并守在旁边。

驾驶方式：不踩油门时，车以约 5 mph 怠速爬行（像自动挡汽车），代表多巴胺神经元自己的基础放电；GABA 刹车把它按在低速，停车要一直踩着刹车。油门 = 你自己的“go”信号（前额叶的谷氨酸）。吃药后刹车变弱（GABA 被抑制），怠速就把车往前推（药物引起、与目标无关的多巴胺上升）；剂量大时踩死刹车也停不下来（去抑制 disinhibition）。同时司机犯困，转向变慢，画面变暗，仪表上 Drowsy 灯亮。路上有抛锚的车、施工路障和红灯：红灯要刹停，等变绿再走，闯红灯算撞车。

真实驾驶：速度用 mph。城区 10 到 30 mph，有红灯和直角急转弯；高速 40 到 65 mph，没有红灯，只有缓弯。超过限速 10 mph 以上持续 3 秒，或低于最低速度且不踩油门持续 10 秒，会被警察拦下（−10）。从高速进城时，“City”牌子之后留有一段减速路段（约 3.5 秒），里面没有红灯、急转弯和金色大门；在牌子前减速不算“太慢”。松油门只是滑行，车速越快滑得越远；只有刹车能快速停下，所以要提前刹车。入弯前要减速到黄色牌子上的建议速度，太快会被甩出路面（算撞车）。城区和高速可以类比不同情境下的“合适状态”：上课、睡觉要平稳，运动可以更兴奋；健康的大脑会自己调节，吃药后车自己往前冲，哪个限速都守不住。规则都和现实开车一样，学生不需要额外记规则。

导航和语音：右下角的导航小地图显示前方路线（弯道、红灯、金色大门、城区/高速分界、障碍物）和几秒后到达；语音会提前播报（英文），仪表栏的 🔊 按钮或 V 键可以关闭，教室里多台电脑同时玩时建议关掉。被警察拦下时，警车会开到你车前；撞车三次或过量时，救护车会开过来，然后显示结果页。

目标和计分：活过 180 天，生命分 (life score) 越高越好。生命分 = 健康天数（车速 60% 到 140% 且呼吸 ≥ 60%，每天 +1）+ 日常奖赏（每个 +5，耐受越高得分越少）+ 通过人生事件（开进金色大门，且车速 60% 到 140%，+10）− 错过人生事件（从旁边绕过、太快或太慢，每次 −20）− 撞车（每次 −15，并失去 1 点健康；3 次撞车进医院，游戏结束）。每次出现药丸，同一排的另一条车道上一定有一个日常奖赏，让学生做选择。吃药和车速本身不加分也不扣分，代价由“大脑”收取：快感期太快、戒断期太慢都不得分，耐受让日常奖赏变淡，错过人生事件，过量直接结束。结束页会列出“没得分的日子”分别花在哪里，可以拿来讨论。

课堂用法（约 10 分钟）：全班先玩 Mode 1 一轮（约 3 分钟），再玩 Mode 2；比一比谁活过 180 天、用了什么策略。然后用右侧“After you play”的 4 个问题讨论。提醒学生这是教学模型：时间被加速，药效在游戏里只持续几秒。结束页有求助热线 (SAMHSA 1-800-662-4357，988)。

Say: “Speed is dopamine. Your score is days alive, not speed.”
Say: “Notice: the pill does not press the gas. It cuts the brakes, and the idling engine does the rest.”
Say: “Disinhibition here means a cell’s brake is released. It does not mean the person loses self-control.”
Say: “Watch the breathing gauge. That is what kills in an overdose.”
Say: “What was your life score? Where did your lost days go: too fast, too slow, or slowed breathing?”

A teaching model, not a medical simulator. Speed, brakes, breathing, tolerance and withdrawal follow simple equations chosen to show the direction of each real effect, not its exact size or timing.

Glossary

Key terms in the six official languages of the United Nations: العربية, 中文, English, Français, Русский and Español. Search in any language, hide the languages you do not need, and choose the language of the definitions.

English definitions follow the rest of this page. Translations were prepared for teaching; standard scientific terms were preferred over literal ones.

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 act at the terminal: cocaine keeps released dopamine around longer, and methamphetamine pushes dopamine out even when the neuron is quiet (Lüscher and Ungless 2006; for gambling, Fiorillo et al. 2003).

Lasting changes

With repeated drug use, the receiving neurons at station 5 change: ΔFosB builds up and switches genes on and off for weeks, and brain scans of people with addiction show fewer D2 receptors. The dopamine neuron at station 1 changes too. These changes help explain why craving can last for months after the drug is gone. Tolerance is different: it fades during a break, so taking an old dose after a break can cause an overdose.

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. Imagine it does 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），留在细胞质里的多巴胺会被 MAO 分解，电信号到达时能释放的多巴胺就少了很多。丁苯那嗪 (tetrabenazine) 正是用这个原理治疗亨廷顿病的不自主运动。可以追问：冰毒也干扰 VMAT2，为什么多巴胺反而上升？因为冰毒还让 DAT 反转，把细胞质里的多巴胺泵出去。这道题检验学生是否理解"每一站各管什么"。

Sources

Show all sourcesshow

Lüscher C, Ungless MA (2006). The mechanistic classification of addictive drugs. PLoS Medicine 3: e437. Link ↗
Nestler EJ (2025). The biology of addiction. Science Signaling 18: eadq0031 (table 1 lists each drug's protein target). Link ↗
Nestler EJ, Lüscher C (2019). The molecular basis of drug addiction: linking epigenetic to synaptic and circuit mechanisms. Neuron 102: 48–59. Link ↗
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 ↗
Johnson SW, North RA (1992). Opioids excite dopamine neurons by hyperpolarization of local interneurons. Journal of Neuroscience 12: 483–488. PubMed ↗
Mansvelder HD, McGehee DS (2002). Cellular and synaptic mechanisms of nicotine addiction. Journal of Neurobiology 53: 606–617. PubMed ↗
Sulzer D, Sonders MS, Poulsen NW, Galli A (2005). Mechanisms of neurotransmitter release by amphetamines: a review. Progress in Neurobiology 75: 406–433. PubMed ↗
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 ↗
Fiorillo CD, Tobler PN, Schultz W (2003). Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299: 1898–1902. Link ↗
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 ↗