Addiction and brain reward and antireward pathways.
Addiction and brain reward and antireward pathways.
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成瘾和大脑奖励和反发达途径。
DOI：
10.1159/000324065
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发表时间：
2011
影响因子：
--
通讯作者：
Gardner EL
中科院分区：
文献类型：
--
作者：
Gardner EL
成瘾性药物的共同点是，它们都是由实验室动物自愿自我给药（通常是贪婪的），而且它们增强了大脑奖赏回路的功能（产生吸毒者所寻求的“兴奋”）。核心奖赏回路由一个“串联”回路组成，该回路通过内侧前脑束连接腹侧被盖区、丘脑核和腹侧苍白球。虽然最初认为这些回路只是编码享乐基调的设定点，但现在认为这些回路在功能上要复杂得多--还编码注意力、奖励预期、奖励预期的不确定性和激励动机。这些回路中的“享乐失调”可能导致成瘾。奖赏回路中的“第二阶段”多巴胺能成分是对成瘾药物敏感的关键成分。所有成瘾性药物都有一个共同点，即它们（直接或间接地，甚至是通过突触）增强丘脑核中的多巴胺能奖赏突触功能。药物自我给药由丘脑核多巴胺水平调节，并将丘脑核多巴胺保持在特定的升高范围内（以维持所需的快感水平）。对于某些类别的成瘾药物（例如，阿片类药物），对欣快效应的耐受性随着长期使用而发展。使用后的焦虑感随后主导了奖赏回路的享乐基调，成瘾者不再使用药物来获得“兴奋”，而只是回到正常状态（“变直”）。在解剖学、神经生理学和神经化学上，调节成瘾药物愉悦效应的脑回路与调节身体依赖性的脑回路以及调节渴望和复发的脑回路不同。对药物成瘾的脆弱性有重要的遗传变异，但环境因素，如压力和社会失败也会改变大脑的奖励机制，从而使成瘾变得脆弱。简而言之，“生物-心理-社会”病因学模型对成瘾非常适用。成瘾似乎与大脑奖励回路中的多巴胺能功能障碍状态有关。对人类的神经影像学研究进一步证实了这一假设。可靠的证据还表明，阿片类物质、内源性大麻素、GABA能和多巴胺能机制也与成瘾有关。重要的是，药物成瘾从偶尔的娱乐使用发展到冲动使用，再到习惯性的强迫使用。这与从奖励驱动到习惯驱动的寻求药物行为的进展有关。这种行为进展与从腹侧纹状体（中脑核）到背侧纹状体控制药物寻求行为的神经解剖学进展相关。三种经典的渴望和复吸触发因素是：a）重新暴露于成瘾药物，B）压力，以及c）重新暴露于先前与吸毒行为相关的环境线索（“人、地方、事物”）。药物引发的复发涉及到脑桥核和神经递质多巴胺。应激触发的复发涉及a）杏仁核的中央核、终纹的床核和神经递质CRF;和B）脑干的外侧被盖去甲肾上腺素能核和神经递质去甲肾上腺素。线索触发的复发涉及杏仁核的基底外侧核、海马和神经递质谷氨酸。神经解剖学，神经生理学，神经化学和神经药理学的知识成瘾药物在大脑中的作用，目前正在产生各种药物成瘾治疗的策略，其中一些似乎是有前途的。
Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly) and that they enhance the functioning of the reward circuitry of the brain (producing the “high” that the drug-user seeks). The core reward circuitry consists of an “in series” circuit linking the ventral tegmental area, nucleus accumbens, and ventral pallidum - via the medial forebrain bundle. Although originally believed to encode simply the set-point of hedonic tone, these circuits are now believed to be functionally far more complex - also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. “Hedonic dysregulation” within these circuits may lead to addiction. The “second-stage” dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dopaminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g., opiates), tolerance to the euphoric effects develops with chronic use. Post-use dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get “high,” but simply to get back to normal (“get straight”). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically, and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the “bio-psycho-social” model of etiology holds very well for addiction. Addiction appears to correlate with a hypo-dopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic, and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are a) re-exposure to addictive drugs, b) stress, and c) re-exposure to environmental cues (“people, places, things”) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter CRF; and b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus, and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising.