成瘾的主要特征是持续存在的心理渴求，即在药物的躯体依赖去除后，成瘾者对药物的心理依赖和对药物愉快体验的记忆仍然长期存在，甚至终生不能消退。已有的研究发现，随着时间的推移，吸毒者的这种心瘾会越来越强，在特定的环境下很容易不顾一切地去吸毒。近期，北京大学中国药物依赖性研究所陆林实验室博士生李艳琴等人通过大鼠条件性位置偏爱模型，成功模拟出成瘾后心理渴求持续存在并逐渐增强这一现象，并发现中央杏仁核细胞外信号调节激酶（ERK）信号通路的激活是产生这一现象的必要条件。这一重要研究成果在近日出版的国际知名学术期刊《神经科学杂志》（The Journal of Neuroscience）上发表。
采用大鼠成瘾模型，经过几次吗啡训练后，大鼠就会对给药的环境产生明显的偏爱，即大鼠会在给药环境中产生对药物的渴求，发生觅药行为。如果不给干预，这种对药物的渴求和对给药环境的偏爱可以保持很长时间，并逐渐增强，即在戒断晚期当大鼠被再次置于与吗啡相关的环境中时，这些大鼠比戒断早期的大鼠表现出对吗啡更强烈的渴求。进一步的研究发现，大脑边缘系统中央杏仁核中的ERK在戒断晚期的活性远远高于戒断早期。李艳琴等人还发现在戒断晚期抑制中央杏仁核中ERK的活性会减少大鼠对吗啡的渴求行为，而抑制基底外侧杏仁核的ERK活性则没有这种作用。而且，在大鼠戒断早期激活中央杏仁核的ERK可加剧它们对吗啡的渴求。
这些结果表明，ERK信号通路是心瘾持续存在和逐渐增强的关键，这不仅有助于科学家认识毒瘾复发的机理，还具有重要的应用价值。吸毒病人出戒毒所后，虽然生理上恢复正常，暂时脱离毒品，但对过去吸毒时愉快记忆仍然强烈，对毒品的渴望会持续存在，在社会上很容易再次吸毒。所以我们不能仅对吸毒者采取隔离措施，而应该针对心瘾的重要信号分子，如ERK，积极开发一些药物，降低吸毒者对药物的渴求，从而减少复吸。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
