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;情感和经济成本是惊人的。这种损害的发生主要是因为成瘾是一种慢性复发性疾病，其中寻求药物和服用药物是通过暴露于压力，药物本身和药物相关线索而反复引发的。当味觉刺激作为线索时，大鼠在与滥用药物（如吗啡或可卡因）配对后避免摄入该味觉线索。几十年来，这种现象被解释为一种条件性味觉厌恶，其中味觉提示与药物的厌恶后果配对。从那以后，我们假设大鼠避免摄入味觉线索，因为味觉线索的价值在预期滥用高回报药物时会变得苍白，就像它在预测获得高可口的蔗糖奖励时一样。在过去的十年里，我们已经积累了相当多的支持这一假设。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，大鼠避免摄入已与滥用药物配对的味觉提示，并且这种避免与应激激素皮质酮的升高以及通常伴随甜味提示摄入的多巴胺峰值的钝化有关。更大的回避的味道提示与更多的可卡因自我管理和更大的药物寻求长期禁欲。最后，药物相关的味觉提示的口内递送诱发厌恶味觉反应性（TR，即，张口），并且更多的张口与对药物的更快响应、更大的负荷和更快获得药物服用行为相关。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提示，因为它与滥用的强效药物相比相形见绌，但随着经验的积累，当味觉提示引起条件厌恶状态（即，撤回）。鉴于对味觉线索的更大回避（以及更大的厌恶性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至关重要。为此，初步数据揭示了一种新的病变部位（丘脑口觉区，TOA），当与滥用药物（例如吗啡或可卡因）配对时，它会选择性地破坏对味觉线索的回避，但当与高度有益的1.0 M蔗糖溶液或推定厌恶剂LiCl配对时，则不会。此外，有证据表明，TOA可能是必不可少的线索诱导戒断药物相关线索的发展。鉴于这些新发现，Specific Aim 1将使用与实验者递送的药物配对的味觉提示来验证病变位置。此后，具体目标2将使用药物自我给药来检验以下假设：TOA损伤不仅会破坏药物诱导的味觉线索回避，还会破坏由此产生的药物寻求和药物服用。最后，具体目标3将测量厌恶性TR行为，沿着其他指标，以测试损伤诱导的行为中断是否伴随着条件厌恶状态开始时的中断。

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.