「快樂荷爾蒙」的真相：為什麼我們不應該將多巴胺胡亂混為一談
資料來源：瑪爾塔·薩拉斯卡 / 2022 年 10 月 10 日 / Medscape / 財團法人台灣紅絲帶基金會編譯
谷歌「多巴胺」(dopamine) 這個詞，你會知道它的綽號是「快樂激素」和「快樂分子」，它是我們大腦中最重要的化學物質之一。隨著《衛報》將其稱為「神經遞質的金·卡戴珊 (Kim Kardashian，註1 )」，多巴胺已成為真正的流行科學寵兒——全球各地的人們都試圖通過多巴胺禁食 (dopamine fasts，註2 ) 和多巴胺著裝 (dopamine dressing , 註3 ) 來提升他們的情緒。
然而，一個世紀前，新發現的多巴胺被視為一種乏味的化學物質，只不過是正腎上腺素(noradrenaline) 的前體。幾位頑固而勤奮的科學家改變了這種觀點。
左旋多巴 (Levodopa)：一種無關緊要的前體
當波蘭生物化學家和維生素發現者 Casimir Funk 於 1911 年首次合成多巴胺前體左旋多巴時，他不知道該分子在藥理學和神經生物學中的重要性。瑞士生物化學家馬庫斯·古根海姆 (Markus Guggenheim) 也沒有，他於 1913 年從蠶豆種子中分離出左旋多巴。古根海姆給一隻兔子服用了 1 克左旋多巴，沒有明顯的負面影響。然後他準備了更大的劑量（2.5 g）並在自己身上進行了測試。 「服用十分鐘後，我感到非常噁心，我不得不嘔吐兩次」，他在論文中寫道。在體內，左旋多巴會轉化為多巴胺，這可能會起到催吐劑的作用——古根海姆對此並不了解。他乾脆放棄了他的人體研究，錯誤地根據他的動物研究得出結論，即左旋多巴在藥理學上相當不重要」。
大約在同一時間，歐洲的幾位科學家成功地合成了多巴胺，但這些發現並沒有大張旗鼓地宣揚而被擱置。在接下來的三十年裡，多巴胺和左旋多巴被推到了學術上的默默無聞之中。就在二戰前夕，一群德國科學家證明左旋多巴在體內代謝為多巴胺，而另一位德國研究人員赫爾曼·布拉施科（Hermann Blaschko）則發現多巴胺是正腎上腺素合成的中間體。然而，即使是這些發現也沒有立即被接受。
多巴胺偵探。上一行，從左到右：Casimir Funk、Arvid Carlsson、Oleh Hornykiewicz。下一行：Markus Guggenheim, Bernard Brodie, Hermann (Hugh) Blaschko。
圖片來源：從左到右：維基百科；亨利.克蒙哥馬利/法新社透過蓋蒂圖片；維基百科；創作共用; NIH;創作共用
多巴胺的故事在戰後幾年加速發展，觀察到這種激素存在於各種組織和體液中，儘管沒有中樞神經系統那麼豐富。 Blaschko 很感興趣，他（在逃離納粹德國，改名為 Hugh，並開始在牛津大學工作）假設多巴胺不可能是正腎上腺素的一個不起眼的前體——它必須有自己的一些生理功能。他請他的博士後研究員 Oheh Hornykiewicz 測試一些想法。 Hornykiewicz 很快證實多巴胺可以降低天竺鼠的血壓，證明多巴胺確實具有獨立於其他兒茶酚胺 (catecholamines) 的生理活性。
利血平(Reserpine)和兔耳
當 Blaschko 和 Hornykiewicz 對多巴胺在體內的生理作用感到困惑時，在大西洋彼岸的美國馬里蘭州國家心臟研究所，藥理學家 Bernard Brodie 及其同事正在為發現多巴胺在大腦中的主要作用奠定基礎。
劇情警示：布羅迪的工作顯示，一種名為利血平的新型精神科藥物能夠完全消耗大腦中的血清素(serotonin)，而且——事實證明——最重要的是——模仿帕金森病典型的神經肌肉症狀。與多巴胺的聯繫將由新的實驗室同事 Arvid Carlsson 建立，他後續將獲得諾貝爾獎。
利血平源自蛇根木 (Rauwolfia serpentina)（一種數百年來在印度被用於治療精神疾病、失眠和蛇咬傷的植物），被引入西方作為治療精神分裂症的藥物。
它效果驚人。 1954 年，媒體稱贊在治療「無可救藥的精神病患者」方面取得的「戲劇性」和看似「不可思議」的結果。然而，利血平有一個缺點。關於該藥物嚴重副作用的報導很快就發生了變化，包括頭痛、頭暈、嘔吐，以及更令人不安的是，模仿帕金森病的症狀，從肌肉僵硬到震顫。
Brodie 觀察到，當注射利血平時，動物變得完全不動。血清素 (Serotonin) 幾乎從他們的大腦中消失了，但奇怪的是，刺激血清素產生的藥物並沒有扭轉兔子的靜止狀態。
卡爾森意識到利血平的副作用一定與其他兒茶酚胺 (catecholamines) 有關，他開始尋找罪魁禍首。他搬回了他的家鄉瑞典並訂購了一個分光光度計 (spectrophotofluorimeter)。在他的一個實驗中，卡爾森給一對兔子注射了利血平，這導致動物變得緊張，耳朵扁平。研究人員給動物注射左旋多巴後，15 分鐘內，兔子開始四處跳來跳去，耳朵驕傲地垂直。「我們和兔子一樣興奮」，卡爾森後來在 2016 年的一次採訪中回憶道。卡爾森意識到，由於兔子的大腦中沒有正腎上腺素，多巴胺的消耗一定是產生利血平的運動抑製作用的直接原因。
圖片來源：艾米莉·貝瑞
懷疑論者的沉默
然而，在 1960 年，醫學界還沒有準備好接受多巴胺只不過是左旋多巴和正腎上腺素之間無聊的中間體。在一次著名的倫敦研討會上，卡爾森和他的兩位同事提出了他們的假設，即多巴胺可能是一種神經遞質，因此與帕金森病有關。他們遭到嚴厲的批評。一些專家說，左旋多巴只不過是一種毒藥。卡爾森後來回憶當時說道，「我們的觀點面臨著一種深刻且幾乎完全一致的懷疑」。
這很快就會改變。早先發現多巴胺降低血壓作用的生化學家霍尼凱維奇利用帕金森病患者的死後大腦測試了卡爾森的想法。卡爾森似乎是對的：與健康的大腦不同，帕金森病患者的紋狀體幾乎不含多巴胺。從 1961 年開始，Hornykiewicz 與神經學家 Walther Birkmayer 合作，將左旋多巴注射到 20 名帕金森病患者體內，並觀察到僵硬、靜止和無語的「奇蹟般地」（儘管是暫時的）改善。
到 1960 年代後期，左旋多巴和多巴胺成為頭條新聞。 1969 年《紐約時報》的一篇文章描述了接受左旋多巴治療的帕金森病患者出現了類似的驚人改善。一個剛到醫院不能說話的病人，雙手緊握，表情僵硬，突然可以大步走進醫生辦公室，甚至可以慢跑。「我可能會說我是一個人」，他告訴記者。儘管這種治療很昂貴——相當於 2022 年的 210 美元——但醫生們卻被要求「多巴」淹沒。時至今日，左旋多巴仍然是治療帕金森病的黃金標準。
仍然被誤解
然而，多巴胺的歷史不僅與帕金森病有關，而且還延伸到精神分裂症和成癮的治療。 20 世紀 40 年代，一位法國軍事外科醫生開始服用一種新的抗組胺藥異丙嗪 (promethazine)，以防止接受手術的士兵休克，他注意到一個奇怪的副作用：士兵會變得欣快但同時異常平靜。
在透過添加氯原子對藥物進行修飾並重新命名為氯丙嗪 (chlorpromazine) 後，它迅速成為治療精神病的首選藥物。當時，沒有人將其與多巴胺聯繫起來。當代醫生認為，它可以透過降低體溫來讓人們平靜下來（當時治療精神疾病的常用方法包括用濕冷的床單包裹病人）。然而，就像利血平一樣，氯丙嗪產生了一系列與帕金森病非常相似的不良副作用。這導致荷蘭藥理學家 Jacques van Rossum 假設多巴胺受體阻斷可以解釋氯丙嗪的抗精神病作用——這一觀點至今仍被廣泛接受。
在 1970 年代，通過對囓齒動物的研究，多巴胺與成癮聯繫在一起，這個新穎的想法在接下來的幾十年裡引起了人們的想像。 1997 年，一篇關於多巴胺的故事《我們如何上癮》登上了《時代》雜誌的封面。
圖片來源：時代雜誌
然而，隨著多巴胺/成癮的關聯變得普遍，它也變得過於簡單化了。根據 2015 年《自然神經科學評論》(Nature Reviews Neuroscience) 上的一篇文章，隨後出現了一波低品質的研究——無法重複，貧乏不足——這導致作者得出結論，我們「沉迷於多巴胺的成癮理論」。幾乎所有陽光下的快樂都歸功於多巴胺，從吃美味的食物和玩電腦遊戲到性、音樂和熱水淋浴。然而，正如最近的科學顯示，多巴胺不僅僅是關於快樂——它是關於酬償的預測、對壓力的反應、記憶、學習，甚至是免疫系統的功能。自 20 世紀初首次合成以來，多巴胺經常被誤解和過於簡單化——現在看來，這個故事正在重演。
在最後一次採訪中，卡爾森於 2018 年去世，享年 95 歲，他警告說不要玩弄多巴胺，尤其是開出對這種神經遞質有抑製作用的藥物。「多巴胺參與了我們大腦中發生的一切——所有它的重要功能」，他說。
在我們如何去處理這樣一個微妙且仍然鮮為人知的系統時我們應該要很謹慎。
主要圖片來源：iStock/Getty Images
圖 1，從左到右：維基百科；亨利.克蒙哥馬利/法新社透過蓋蒂圖片；維基百科；創作共用; NIH;創作共用
圖 2：艾米莉·貝瑞
圖 3：時代雜誌
Medscape 醫學新聞 © 2022
註1，金·卡戴珊 (Kim Kardashian) ：金伯莉·諾埃爾·卡戴珊 是一位電視名人、名媛、演員、商人及模特。卡戴珊第一次獲得媒體關注是因為她曾是名媛芭黎絲·希爾頓的助理和朋友，但之後和歌手Ray J在2002年所拍攝的性愛影片「超級明星金·卡戴珊」於2007年遭到外傳才獲得大量關注。
註2，多巴胺禁食 (dopamine fasts) ：多巴胺禁食是世界科技中心矽谷流行的一種生活方式趨勢，它包括讓自己在 24 小時內遠離幾乎所有的刺激。
在此期間，您不能吃或喝除水以外的任何東西，也不能使用互聯網、手機、電腦或電視（或任何其他銀幕或技術）。 你也不能聽音樂或收音機，不能做愛或手淫，我們鼓勵你盡量少讀書和說話。
它的名字指的是多巴胺，一種我們大腦中的化學物質。 科學家們對它的工作原理沒有達成一致，但當有好事發生或我們感到有回報時，它就會被激活。
「禁食」的擁護者說，我們都被媒體和分心的事物壓得喘不過氣來，以至於我們不斷地受到多巴胺的「打擊」，所以我們對它們變得麻木了。 他們認為，通過休息一下，當我們再次開始做這些常規事情時，我們可能會變得更加專注和高效。 然而，其他人則說這是不科學的垃圾。
註3，多巴胺著裝 (dopamine dressing) ：「多巴胺著裝」是由國際時尚專家和心理學家命名的 2022 年流行趨勢，它承諾樂趣、美學、創造力和良好的心理健康。
從科學上講，多巴胺是體內的一種化學信使，它可以創造一種記憶、動力和快樂的感覺——我們需要更多。來自《實驗社會心理學雜誌》的 Hajo Adam 和 Adam Galinsky 的一項研究也證明，一個人的著裝可能會直接影響一個人的自信和心理過程。
多巴胺著裝取決於一個人的心情和幸福，而不是別人的認可。
The Truth About the ‘Happy Hormone’: Why We Shouldn’t Mess With Dopamine
Marta Zaraska / October 10, 2022 / Medscape
Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling — people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.
A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
Levodopa: An Indifferent Precursor
When Casimir Funk, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic — an effect Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”
Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next three decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.
The Dopamine Detectives. Top row, left to right: Casimir Funk, Arvid Carlsson, Oleh Hornykiewicz. Bottom row: Markus Guggenheim, Bernard Brodie, Hermann (Hugh) Blaschko.
The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline — it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, to test a few ideas. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
Reserpine and Rabbit Ears
While Blaschko and Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.
Spoiler alert: Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and ― of greatest significance, as it turned out — mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, who would go on to win a Nobel Prize.
Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.
It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible” results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.
Brodie observed that when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.
Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Carlsson later recalled in a 2016 interview. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
Skeptics Are Silenced
In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”
That would soon change. Hornykiewicz, the biochemist who had earlier discovered dopamine’s blood pressure–lowering effects, tested Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Carlsson was right: unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.
By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive — equivalent to $210 in 2022 — physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
Still Misunderstood
The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.
After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects — an idea that remains widely accepted today.
In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.
Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed — nonreplicated, insufficient — which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure — it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified — and it seems the story is repeating itself now.
In one of his final interviews, Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains ― all its important functions,” he said.
We should be careful how we handle such a delicate and still little-known system.
Credits:
Lead image: iStock/Getty Images
Image 1, L to R: Wikipedia; Henrik Montgomery/AFP via Getty Images; Wikipedia; Creative Commons; NIH; Creative Commons
Image 2: Emily Berry
Image 3: Time magazine
Medscape Medical News © 2022
Cite this: The Truth About the ‘Happy Hormone’: Why We Shouldn’t Mess With Dopamine – Medscape – Oct 10, 2022.