成癮的主要特征是持續(xù)存在的心理渴求,，即在藥物的軀體依賴去除后,，成癮者對藥物的心理依賴和對藥物愉快體驗的記憶仍然長期存在，甚至終生不能消退,。已有的研究發(fā)現(xiàn),，隨著時間的推移，吸毒者的這種心癮會越來越強,，在特定的環(huán)境下很容易不顧一切地去吸毒,。近期，北京大學中國藥物依賴性研究所陸林實驗室博士生李艷琴等人通過大鼠條件性位置偏愛模型,，成功模擬出成癮后心理渴求持續(xù)存在并逐漸增強這一現(xiàn)象,，并發(fā)現(xiàn)中央杏仁核細胞外信號調(diào)節(jié)激酶（ERK）信號通路的激活是產(chǎn)生這一現(xiàn)象的必要條件。這一重要研究成果在近日出版的國際知名學術(shù)期刊《神經(jīng)科學雜志》（The Journal of Neuroscience）上發(fā)表,。
采用大鼠成癮模型,，經(jīng)過幾次嗎啡訓練后，大鼠就會對給藥的環(huán)境產(chǎn)生明顯的偏愛,，即大鼠會在給藥環(huán)境中產(chǎn)生對藥物的渴求,，發(fā)生覓藥行為,。如果不給干預，這種對藥物的渴求和對給藥環(huán)境的偏愛可以保持很長時間,，并逐漸增強,，即在戒斷晚期當大鼠被再次置于與嗎啡相關(guān)的環(huán)境中時，這些大鼠比戒斷早期的大鼠表現(xiàn)出對嗎啡更強烈的渴求,。進一步的研究發(fā)現(xiàn),，大腦邊緣系統(tǒng)中央杏仁核中的ERK在戒斷晚期的活性遠遠高于戒斷早期。李艷琴等人還發(fā)現(xiàn)在戒斷晚期抑制中央杏仁核中ERK的活性會減少大鼠對嗎啡的渴求行為,，而抑制基底外側(cè)杏仁核的ERK活性則沒有這種作用,。而且，在大鼠戒斷早期激活中央杏仁核的ERK可加劇它們對嗎啡的渴求,。
這些結(jié)果表明,，ERK信號通路是心癮持續(xù)存在和逐漸增強的關(guān)鍵，這不僅有助于科學家認識毒癮復發(fā)的機理,，還具有重要的應(yīng)用價值,。吸毒病人出戒毒所后，雖然生理上恢復正常,，暫時脫離毒品,，但對過去吸毒時愉快記憶仍然強烈，對毒品的渴望會持續(xù)存在,，在社會上很容易再次吸毒,。所以我們不能僅對吸毒者采取隔離措施，而應(yīng)該針對心癮的重要信號分子,，如ERK,，積極開發(fā)一些藥物，降低吸毒者對藥物的渴求,，從而減少復吸,。（生物谷Bioon.com）
生物谷推薦原始出處：
The Journal of Neuroscience，28(49):13248-13257,，Yan-Qin Li,，Lin Lu
Central Amygdala Extracellular Signal-Regulated Kinase Signaling Pathway Is Critical to Incubation of Opiate Craving
Yan-Qin Li,1 * Fang-Qiong Li,1 * Xiao-Yi Wang,1 Ping Wu,1 Mei Zhao,1 Chun-Mei Xu,1 Yavin Shaham,2 and Lin Lu1
1National Institute on Drug Dependence, Peking University, Beijing 100083, China, and 2Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224
Cue-induced drug-seeking in rodents progressively increases after withdrawal from operant self-administration of cocaine, heroin, methamphetamine, and alcohol, a phenomenon termed "incubation of drug craving." Here, we used the opiate drug morphine and explored whether incubation of drug craving also occurs in a pavlovian conditioned place preference (CPP) procedure in which rats learn to associate drug effects with a distinct environmental context. We also explored the role of amygdala extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in this incubation. We found that the expression of morphine CPP progressively increases over the first 14 d after the last drug exposure in rats receiving four pairings of low-dose (1 or 3 mg/kg) but not high-dose (10 mg/kg) morphine with a distinct environment. The progressive increase in low-dose (3 mg/kg) morphine CPP was associated with increased ERK phosphorylation (a measure of ERK activity) and CREB (a downstream target of ERK) phosphorylation in central but not basolateral amygdala. Furthermore, inhibition of central but not basolateral amygdala ERK and CREB phosphorylation by U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] decreased the enhanced (incubated) drug CPP after 14 d of withdrawal from morphine. Finally, stimulation of central amygdala ERK and CREB phosphorylation by NMDA enhanced drug CPP after 1 d of withdrawal from morphine, an effect reversed by U0126. These findings indicate that the rat's response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 d of withdrawal from low but not high morphine doses. Additionally, this "incubation of morphine craving" is mediated by acute activation of central amygdala ERK pathway.
