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

描述（由申请人提供）：成瘾对成瘾者、他们的家庭和整个社会都是毁灭性的；情感上和经济上的代价是惊人的。这种损害之所以发生，是因为成瘾是一种慢性复发的疾病，在这种疾病中，药物寻求和药物服用是由于暴露于压力、药物本身和与药物相关的线索而反复开始的。当味觉刺激作为线索时，大鼠会避免摄入与吗啡或可卡因等滥用药物配对的味觉线索。几十年来，这种现象被解释为一种条件性的味觉厌恶，其中味觉暗示与药物的厌恶后果相匹配。我们已经假设，老鼠避免摄入味觉线索，是因为味觉线索的价值在预期高回报的滥用药物时变得苍白，就像它在预测获得高美味的蔗糖奖励时变得苍白一样。在过去的十年里，我们为这个假设积累了大量的支持。然而，与此同时，我们也发现了厌恶的证据。已发表的数据显示，大鼠会避免摄入与滥用药物相关的味觉线索，这种避免与应激激素、皮质酮的升高以及通常伴随摄入甜味线索的伏隔核多巴胺峰值的减弱有关。对味觉线索的回避程度越高，可卡因的自我服用程度越高，长期戒断后寻求毒品的程度也越高。最后，口服药物相关味觉线索引起厌恶味觉反应（TR，即张口），张口越多，对药物的反应越快，负荷越大，吸毒行为习得越快。鉴于这些数据，我们的工作假设是，虽然大鼠最初避免摄入味觉线索，因为它与强效滥用药物相比显得苍白，但随着经验的积累，味觉线索被避免，因为它会引发条件厌恶状态（即戒断）的发作。考虑到对味觉线索的更大回避（以及更大的厌恶TR）与更大的药物寻求和药物服用有关，我们确定潜在的神经回路是至关重要的。为此，初步数据揭示了一个新的损伤部位（丘脑口感觉区，TOA），当与滥用药物（如吗啡或可卡因）配对时，它会选择性地破坏对味觉线索的回避，但当与高回报的1.0 M蔗糖溶液或假定的厌恶剂（LiCl）配对时则不会。此外，有证据表明，在出现药物相关线索后，TOA可能对线索诱导戒断的发展至关重要。鉴于这些新发现，Specific Aim 1将使用味觉线索与实验者递送的药物配对来验证病变位置。之后，Specific Aim 2将使用药物自我给药来验证TOA病变不仅会破坏药物引起的味觉提示回避，还会破坏由此产生的药物寻找和药物服用的假设。最后，Specific Aim 3将测量厌恶的TR行为以及其他指标，以测试病变诱导的行为中断是否伴随着条件厌恶状态的发作中断。

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. PUBLIC HEALTH RELEVANCE: Drug addiction is a devastating chronic relapsing disorder and cues are potent initiators of relapse, in part because they elicit the onset of an aversive affective state. The present proposal tests the hypothesis that an intact thalamic trigeminal orosensory area (TOA) is essential for drug-induced devaluation of natural reward and cue-induced withdrawal. This study will further our understanding of the development of addiction and the underlying neurocircuitry.