IS THE PLANET SHAKING
OR IS IT JUST ME?
咖啡因的作用機轉，為人熟知的就是透過阻斷腦中的腺苷受體。腺苷是細胞消耗能量後的產物（缺血時也可由神經直接產生)，在腦中會產生抑制神經活性、促進放鬆和睡眠的效果。
It’s known that caffeine’s stimulant effect comes from blocking adenosine receptors in the brain. Adenosine is a product of energy consumption (can also be released directly from neurons under conditions like ischemia), which slows down neural activity and promotes relaxation and sleepiness.
咖啡因的結構與腺苷相似，在大腦中就可以對腺苷受體發揮競爭性抑制的作用。咖啡因對腺苷受體的親和力並沒有比腺苷高，但藉著佔走腺苷的結合位，咖啡因就能產生抑制腺苷作用的效果。簡言之就是咖啡因降低了大腦對疲勞的感知能力。
As it’s structurally similar to adenosine, caffeine acts as a competitive inhibitor of adenosine receptors in the brain. Although caffeine does not have a higher affinity than adenosine for adenosine receptors, by binding to and occupying the same binding site, caffeine can effectively inhibit the effects of adenosine. Simply put, caffeine reduces perceived exertion.
但長期喝咖啡和偶爾才喝，兩者會產生不同效果嗎？
首先，我們必須定義急性/慢性攝取咖啡因。
But will it affect differently with long-term consumption?
First, we must define acute/long-term caffeine intake.
急性攝取咖啡因就如字面意思，特別指無喝咖啡習慣，只在特定時間攝取咖啡因的情形，例如只有上台報告前才喝，只有開重大會議前才喝，平常不喝咖啡。
Acute caffeine intake, as the term suggests, refers to consuming caffeine at a specific point in time, such as when you might drink coffee before a presentation or an important meeting, but not otherwise.
慢性攝取就比較複雜了，有些試驗可能會做每日攝取的投食方式，也有的是隔一天才給予一次咖啡因，持續一段較長的時間之後，再跟對照組作比較。
Long-term caffeine intake has more variable approaches. Some studies might administer caffeine daily, or they might administer it on an interval basis. After a prolonged period of administration, the results are compared to a control group.
急性攝取咖啡因可以使人反應更快，增強大腦對獎勵的反應（負增強>正增強），並同時產生促進和抑制多巴胺相關運動功能的作用。主要是由於增加多巴胺的釋放，增強D1多巴胺受體訊號傳導 (透過A1腺苷受體)，以及增強D2多巴胺受體的訊號傳導 (透過A2A腺苷受體)。
Acute caffeine intake can induce faster reaction and enhance brain responses to reward (negative reinforcement > positive reinforcement), both promote and inhibit dopamine-related motor functions. Acute caffeine enhances dopamine release, D1 receptor signalling (via A1 receptor), and D2 receptor signalling via A2A receptor.
急性咖啡因攝取對多巴胺神經路徑同時有促進和抑制效果，是因為多巴胺受器也分好幾種功能和分布位置不同的亞型。
Acute caffeine intake has both stimulatory and inhibitory effects on dopamine pathways because dopamine receptors have several subtypes with different functions and sites of distribution.
正增強是「這麼做的話，會得到好處」，負增強是「這麼做的話，才能免於受到痛苦的威脅」。例如集點卡是正增強，提早出門以避開塞車是負增強。(其實我一直覺得付費移除廣告是負增強) 負增強也會讓攝取咖啡因變得有點像物質成癮的情形——因為怕停止抽菸後的戒斷症狀而繼續抽，因為怕酒精消退後要面對的事情而繼續喝酒，擔心如果咖啡因攝取不足會發生什麼，所以繼續喝咖啡。
Positive reinforcement encourages desired behaviours by adding a desirable stimulus after the behaviour occurs. Negative reinforcement encourages a behaviour by taking away something unpleasant. For example, saving reward points is a kind of positive reinforcement, while leaving for work early to avoid traffic can be cultivated through negative reinforcement. (by the way, I always think that paying to remove ads is negative reinforcement) Negative reinforcement can also make caffeine use a bit like substance addiction—you continue smoking because you fear the withdrawal symptoms, and you continue drinking because you fear the thing you face after the alcohol wears off, fear of what might happen if you don't consume enough caffeine so you keep drinking it.
長期攝取咖啡因，由於試驗方法不同，結果並不一致。有些試驗觀察到受試者在長期每日攝取咖啡因後反應速度減慢，多巴胺相關的運動功能抑制作用較顯著。另外也因為A1受體刺激的獎賞路徑降低了，相較之下A2A受體增強D2受體的訊號傳遞就增強了。
Long-term caffeine consumption has inconsistent results due to different study methods. In some studies, slower reaction and more profound inhibition of dopamine-related motor function were observed with long-term daily caffeine intake. Moreover, the reward pathway through A1R decreased, while D2R signalling via A2AR enhanced.
咖啡因攝取若變成一種慣性，會使腦神經細胞需要更高程度的刺激，才能達到同等程度的反應水準。這可能和腺苷受體、多巴胺受體的反應產生改變，以及彼此之間的互動也發生改變有關。
When caffeine intake becomes a habit, brain neurons require higher levels of stimulation to achieve the same level of response. This may be related to changes in the response of adenosine and dopamine receptors, as well as changes in the interaction between them.
從認知心理學角度出發的研究也納入了「環境」對攝取咖啡因的影響，發現在動盪的環境，攝取咖啡因能讓人反應更敏捷、思想更活躍、強化學習力也提升了；但在單調、穩定的環境下，攝取咖啡因會使人變得過度專注於平凡的事物，並削弱基於獎賞的判斷力。
Research from a cognitive psychology perspective has also taken into account the impact of "environment" on caffeine consumption. It has been found that in volatile circumstances, caffeine can make people more agile and active in thinking, and enhance reinforcement learning. But in stable circumstances, caffeine can make people overly concerned about ordinary things and impair reward-based judgment.
咖啡因增強大腦反應的效果，可能來自對兩個正增強物或兩個負增強物之間不同強度的敏感性增加，這有利於在動蕩的情況下做出基於獎賞的判斷。
Increased brain response might result from elevated sensitivity towards different reinforcement strengths between two positive or two negative reinforcers, which benefits reward-based judgment in a volatile circumstance.
在單調情況下，咖啡因會使正增強刺激與負增強刺激之間的區辨力下降，導致過份執著微小差異，產生類似病理性D2R過度活躍和多巴胺訊號失調時的「異常顯著性」(aberrant salience) 症狀，容易誤判中性刺激的重要性和錯誤歸因。這在急性咖啡攝取最顯著。
In a stable circumstance, caffeine reduced the specificity between a positive vs a negative reinforcer, which could result from overweighing nuisances. It mimics the aberrant salience (misattribution of importance to neutral stimuli) under pathological D2R hyperactivity and dysregulated dopamine signalling. This is most pronounced with acute caffeine intake.
腺苷受體有A1、A2A、A2B和A3四種亞型，有不同的功能和分佈。A1和A2A受體主要在中樞神經系統，調節神經傳導物質的釋放並影響睡眠；而A2B和A3受體則在周邊組織調節發炎和免疫反應。
Adenosine receptors have four subtypes-A1, A2A, A2B, and A3, which have distinct functions and distributions within the body. A1 and A2A receptors are primarily involved in the central nervous system, regulating neurotransmitter release and influencing sleep, while A2B and A3 receptors are more prominent in peripheral tissues, playing roles in inflammation and immune responses.
咖啡因對腺苷受體的A1型和A2A型親和力差不多，會同時對這兩個受體的產生抑制作用。而咖啡因提神的作用主要是透過抑制A2A受體；由於A2A受體可以和D2R受體形成複合體，D2R是神經抑制作用的多巴胺受體亞型，因此抑制A2A受體就抑制了D2R對多巴胺神經的抑制。「喝咖啡改善帕金森氏症」可能和這條路徑有關。
Caffeine presents roughly equal affinity for A1 and A2A receptors, and it antagonizes adenosine's actions at both. Caffeine promotes wakefulness primarily involves blocking the A2A receptors. Because they form A2A-D2R heteromers, and D2R inhibit neuronal excitability when activated, inhibiting A2A receptors inhibits the inhibition of D2R on dopamine neurons. "Drinking coffee improves Parkinson's disease" may be related to this pathway.
A1受體參與調節神經元興奮性和突觸傳遞，阻斷這些受體可能導致神經放電增加，加劇焦慮或其他類似興奮劑的效應，尤其是在A1受體較為普遍的情況。腦中A1受體分佈密度較高的人，喝咖啡後可能比較容易感受到焦慮、失眠或其他不良副作用。
A1 receptors are involved in regulating neuronal excitability and synaptic transmission. Blocking these receptors can lead to increased neuronal firing and potentially heightened anxiety or other stimulant-like effects, especially when A1 receptors are more prevalent. A higher density of A1 receptors in the brain may lead to a greater likelihood of experiencing adverse effects from caffeine intake.
長期攝取咖啡因會導致腺苷受體的表現發生變化，並可能因慢性拮抗作用而增加或增敏A1受體，導致耐受性和戒斷症狀。A1和A2A受體之間以及與其他神經傳導物質（多巴胺、GABA、麩胺酸）之間也會相互作用。咖啡因對個體產生的影響取決於這些交互作用的平衡。
Long-term caffeine consumption can lead to changes in adenosine receptor expression, potentially upregulating A1 receptors in response to chronic antagonism. This upregulation may contribute to tolerance and withdrawal symptoms. A1 and A2A receptors can also interact with each other and with other neurotransmitter systems (dopaminergic, GABAergic, glutamatergic neurons). The net effect of caffeine on an individual depends on the balance of these interactions.
*.＊ 𓈒𓂂𓏸
由於咖啡飲品的成份很複雜，探討咖啡因機轉的科學研究為了量化和控制變數，會採取給受試者咖啡因膠囊的方式而不是喝咖啡。劑型本身就會有影響，例如飲用咖啡是透過消化系統傳遞咖啡因，釋放速度更慢、更持久；而咖啡因口香糖是透過口腔黏膜傳遞咖啡因，吸收速度更快、效果也更快顯現。咖啡香透過嗅覺神經，能刺激到與情緒和記憶有關的腦區。
體重不同、動腦程度不同、腦中接受器的亞型密度不同、喝法不同、攝取方式不同，所以就算能照著科學研究背書的建議劑量和方式去攝取咖啡因，也許結果也不如預期。只能說，咖啡因相關研究的結果不能直接作為日常飲用咖啡的依據。至於到底要不要喝咖啡? 又要怎麼喝? 嗯吶 —— 高興怎麼喝，就怎麼喝囉。
๋𓈒𓂂 𓈒⭑°ೃ࿔*:･
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