Role of the Trigeminal Orosensory Area of the Thalamus in Natural and Drug Reward

描述(由申请者提供)：上瘾对成瘾者、他们的家庭和整个社会都是毁灭性的；情感和经济代价令人震惊。这种损害很大程度上是因为成瘾是一种慢性复发的疾病，在这种疾病中，寻求毒品和吸毒是由于暴露在压力、药物本身和与药物相关的线索中反复引发的。当味觉刺激作为线索时，大鼠在与吗啡或可卡因等滥用药物配对后，会避免摄入这种味觉线索。几十年来，这种现象被解释为一种条件性的味觉厌恶，即味觉提示与药物的厌恶后果相匹配。自那以后，我们一直假设大鼠避免摄入味觉线索，因为在预期滥用这种极具回报的药物时，味觉线索的价值相形见绌，就像预测获得高度可口的蔗糖奖赏时一样。在过去的十年里，我们为这一假说积累了相当多的支持。然而，与此同时，我们也发现了厌恶情绪的证据。公布的数据显示，大鼠避免摄入与滥用药物配对的味觉线索，这种回避与压力荷尔蒙和皮质酮的升高以及伏隔区多巴胺峰值的钝化有关，而伏隔多巴胺峰值通常伴随着甜味线索的摄入。更多地避免味觉提示与更多的可卡因自我管理和长期戒除后更多的寻求药物相关。最后，口腔内传递与药物相关的味觉线索会引起厌恶的味觉反应(TR，即张口)，更多的张口与对药物的更快反应、更大的负荷和更快的吸毒行为相关。考虑到这些数据，我们的工作假设是，虽然大鼠最初避免摄入味觉线索，因为与强有力的滥用药物相比，它相形见绌，但有了经验，当味觉线索引发条件性厌恶状态(即戒断)的开始时，它是避免的。鉴于更多地避免味觉提示(以及更多厌恶的tr)与更多的寻求毒品和吸毒有关，我们识别潜在的神经回路是至关重要的。为此，初步数据显示了一个新的病变部位(丘脑口感区域，TOA)，当与吗啡或可卡因等滥用药物配合使用时，它会选择性地扰乱味觉线索的避免，但当与回报很高的1.0M蔗糖溶液或公认的厌恶剂LiCl配合使用时，则不会。此外，有证据表明，在呈现药物相关线索后，TOA可能在线索诱发戒断的发展过程中起着至关重要的作用。鉴于这些新的发现，特定的目标1将使用味觉提示与实验者交付的药物配对，以验证病变的位置。此后，特定目标2将使用药物自我给药来测试这一假设，即TOA损伤不仅会扰乱药物诱导的味觉回避，而且还会扰乱由此产生的药物寻找和吸毒。最后，特定目标3将测量厌恶的tr行为，以及其他指数，以测试病变诱导的行为中断是否伴随着条件性厌恶状态的开始中断。

DESCRIPTION (provided by applicant): Addiction can be devastating for addicts, their families, and society as a whole; the emotional and economic costs are astounding. Much of this damage occurs because addiction is a disease of chronic relapse where drug-seeking and drug-taking are repeatedly initiated by exposure to stress, the drug itself, and drug-associated cues. When a gustatory stimulus serves as the cue, rats avoid intake of that taste cue following pairing with a drug of abuse such as morphine or cocaine. For decades, this phenomenon was interpreted as a conditioned taste aversion where a taste cue was paired with the aversive consequences of a drug. We have since hypothesized that rats avoid intake of the taste cue because the value of the taste cue pales in anticipation of the highly rewarding drug of abuse, much as it pales when predicting access to a highly palatable sucrose reward. In the last decade, we have amassed considerable support for this hypothesis. At the same time, however, we also have uncovered evidence for aversion. Published data reveal that rats avoid intake of a taste cue that has been paired with a drug of abuse, and this avoidance is associated with an elevation of the stress hormone, corticosterone, and blunting of the accumbens dopamine peak that normally accompanies ingestion of the sweet taste cue. Greater avoidance of the taste cue is correlated with greater cocaine self-administration and with greater drug-seeking following prolonged abstinence. Finally, intraoral delivery of the drug-associated taste cue elicits aversive taste reactivity (TR, i.e., gapes) and more gaping is associated with faster responding for drug, greater load up, and faster acquisition of drug taking behavior. Given these data, our working hypothesis is that, while rats initially avoid intake of the taste cue because it pales in comparison to the potent drug of abuse, with experience the taste cue is avoided as it comes to elicit the onset of a conditioned aversive state (i.e., withdrawal). Given that greater avoidance of the taste cue (and greater aversive TR) has been linked to greater drug-seeking and drug-taking, it is critical that we identify the underlying neurocircuitry. To this end, preliminary data have revealed a novel lesion site (thalamic orosensory area, TOA) that selectively disrupts avoidance of a taste cue when paired with a drug of abuse, such as morphine or cocaine, but not when paired with a highly rewarding 1.0 M sucrose solution or a putatively aversive agent, LiCl. Further, evidence suggests that the TOA may be essential for the development of cue-induced withdrawal following presentation of the drug-associated cue. Given these new findings, Specific Aim 1 will use a taste cue paired with experimenter delivered drug to verify lesion placement. Thereafter, Specific Aim 2 will use drug self-administration to test the hypothesis that the TOA lesion will disrupt not only drug-induced avoidance of the taste cue, but the resultant drug-seeking and drug-taking as well. Finally, Specific Aim 3 will measure aversive TR behavior, along with other indices, to test whether the lesion-induced disruption in behavior is accompanied by a disruption in the onset of the conditioned aversive state.