An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction.
An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction.
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DOI：
10.1038/npp.2009.142
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发表时间：
2010-01
影响因子：
7.6
通讯作者：
Akil, Huda
中科院分区：
文献类型：
--
作者：
Flagel, Shelly B.;Robinson, Terry E.;Clark, Jeremy J.;Clinton, Sarah M.;Watson, Stanley J.;Seeman, Phillip;Phillips, Paul E. M.;Akil, Huda
根据对新环境的高或低反应性选择性饲养的大鼠，其特征在于其他被认为与成瘾易感性相关的行为和神经生物学特征。这两种动物的自我给药倾向不同，它们对与奖励相关的线索的价值、冲动行为和多巴胺系统也不同。当提示与食物或可卡因奖励配对时，高反应大鼠（bHR）学会了接近提示，而低反应大鼠（bLR）学会了接近食物递送的位置，这表明bHR而不是bLR将激励价值归因于提示。此外，虽然在“冲动选择”的测量中不那么冲动，但bHR在“冲动行为”的测量中更冲动-即他们难以为了获得奖励而抑制行为，这表明“行为去抑制”。多巴胺激动剂喹吡罗引起更大的bHR相对于bLR的精神活动，表明多巴胺超敏。事实上，相对于bLR，bHR也有更大比例的多巴胺D2 high受体，功能活性形式的受体，在纹状体，尽管较低的D2 mRNA水平和可比的总D2结合。此外，快速扫描循环伏安法显示，bHRs有更多的自发多巴胺“释放事件”的核心的核突触比bLR。因此，bHRs表现出类似于人类的“外化障碍”，代表了成瘾脆弱性的遗传动物模型，该模型与将激励显着性归因于奖励相关线索、行为去抑制和多巴胺能“音调”增加的倾向相关。
Rats selectively-bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, while less impulsive on a measure of “impulsive choice”, bHRs were more impulsive on a measure of “impulsive action”— i.e. they had difficulty withholding an action in order to receive a reward, indicative of “behavioral disinhibition”. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2high receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine “release events” in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to “externalizing disorders” in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic “tone”.
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