Neurocircuitry of alcohol addiction: synthesis from animal models.
Neurocircuitry of alcohol addiction: synthesis from animal models.
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DOI：
10.1016/b978-0-444-62619-6.00003-3
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Koob, George F
中科院分区：
文献类型：
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作者：
Koob, George F
酒精中毒，更一般地说是药物成瘾，可以被定义为一种慢性复发性疾病，其特征在于：（1）强迫寻求和服用药物（酒精）;（2）限制（酒精）摄入量的失控;以及（3）出现负面情绪状态（例如，烦躁不安、焦虑、易怒），反映了一种动机性戒断综合征，当获得药物（酒精）被阻止时（此处定义为依赖）。与酗酒相关的强迫性药物寻求可以来自多种神经适应，但本文认为，主要来自动物模型，一个关键组成部分涉及大脑奖励功能下降，大脑应激功能增加，以及执行功能受损，所有这些都有助于负强化的构建。负强化被定义为服用药物，消除负面的情绪状态。驱动这种负强化的负面情绪状态被假设来自腹侧纹状体中奖赏神经传递的减少，例如腹侧纹状体中多巴胺和阿片肽功能的减少，但也来自大脑应激系统的招募，例如杏仁核中的促肾上腺皮质激素释放因子（CRF）。支持这一论点的动物模型数据表明，急性戒断慢性酒精，足以产生依赖，增加奖励阈值，增加焦虑样反应，降低多巴胺系统功能，并增加细胞外水平的CRF中央核杏仁核。CRF受体拮抗剂也可阻断由依赖性产生的过量药物摄入。酒精中毒还涉及大量的神经适应，这些神经适应在急性戒断后持续存在，并引发复发和认知功能的缺陷，这些缺陷也会引发强迫性饮酒。大脑应激反应系统被假设为被急性过量药物摄入激活，在反复戒断过程中被敏化，持续到长期禁欲，并促成酒精中毒的强迫性。与CRF相互作用的延伸杏仁核中的脑应激系统的其他成分可能有助于戒断的负性动机状态，包括去甲肾上腺素功能的增加、强啡肽活性的增加和神经肽Y的减少。奖赏回路功能受损和大脑应激系统回路的募集相结合，为负性情绪状态提供了强大的神经化学基础，负性情绪状态是负性强化的原因，而负性强化又驱动了酗酒的强迫性。
Alcoholism, more generically drug addiction, can be defined as a chronically relapsing disorder characterized by: (1) compulsion to seek and take the drug (alcohol); (2) loss of control in limiting (alcohol) intake; and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability), reflecting a motivational withdrawal syndrome, when access to the drug (alcohol) is prevented (defined here as dependence). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here, derived largely from animal models, is that a key component involves decreased brain reward function, increased brain stress function, and compromised executive function, all of which contribute to the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from decreases in reward neurotransmission in the ventral striatum, such as decreased dopamine and opioid peptide function in the nucleus accumbens (ventral striatum), but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Data from animal models that support this thesis show that acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. Alcoholism also involves substantial neuroadaptations that persist beyond acute withdrawal and trigger relapse and deficits in cognitive function that can also fuel compulsive drinking. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include increases in norepinephrine function, increases in dynorphin activity, and decreases in neuropeptide Y. The combination of impairment of function in reward circuitry and recruitment of brain stress system circuitry provides a powerful neurochemical basis for the negative emotional states that are responsible for the negative reinforcement that drives the compulsivity of alcoholism.