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

丘脑三叉神经口感觉区在自然和药物奖赏中的作用

• 批准号: 8265862
• 负责人: Jennifer E. Nyland
• 金额: $ 2.27万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265862
• 关键词: Abstinence; Address; Affective; Anxiety; Area; Attenuated; Behavior; Chronic; Chronic Disease; Cocaine; Corticosterone; Cues; Data; Development; Disease; Dopamine; Drug Addiction; Drug usage; Emotional; Essential Drugs; Exposure to; Family; Frequencies; Heroin; Hormones; Hour; Infusion procedures; Ingestion; Intake; Learning; Lesion; Link; Measures; Mental Depression; Methodology; Morphine; Oral Administration; Pharmaceutical Preparations; Posterior Thalamic Nuclei; Publishing; Rattus; Relapse; Rewards; Role; Saccharin; Self Administration; Self-Administered; Site; Societies; Solutions; Stimulus; Stress; Sucrose; Swimming; Taste Perception; Testing; Thalamic structure; Time; Trigeminal System; Withdrawal; Work; addiction; aversive conditioning; base; craving; drug of abuse; drug relapse; drug reward; economic cost; experience; indexing; new technology; novel; prevent; sweet taste perception

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.

描述（由申请人提供）： 成瘾对成瘾者、他们的家庭和整个社会来说可能是毁灭性的；情感和经济成本是惊人的。造成这种损害的大部分原因是成瘾是一种慢性复发的疾病，寻求药物和吸毒是由于暴露于压力、药物本身和与药物相关的暗示而反复引发的。当味觉刺激作为提示时，老鼠在与吗啡或可卡因等滥用药物配对后会避免摄入该味觉提示。几十年来，这种现象被解释为一种条件性味觉厌恶，即味觉提示与药物的厌恶后果相结合。此后，我们假设老鼠会避免摄入味觉提示，因为味觉提示的价值在预期滥用高回报药物时会显得苍白，就像在预测获得高度美味的蔗糖奖励时它会显得苍白一样。在过去的十年中，我们已经为这一假设积累了相当多的支持。但与此同时，我们也发现了厌恶的证据。已发表的数据显示，老鼠会避免摄入与滥用药物相伴的味觉提示，这种回避与应激激素、皮质酮的升高以及伏隔核多巴胺峰值的减弱有关，而伏隔核多巴胺峰值通常伴随着甜食的摄入味觉提示。对味觉提示的更大程度的回避与更多的可卡因自我施用以及长期戒断后更多的药物寻求相关。最后，口腔内传递与药物相关的味觉提示会引起厌恶的味觉反应（TR，即打哈欠），并且更多的张开与对药物的更快反应、更大的负荷和更快地获得吸毒行为相关。鉴于这些数据，我们的工作假设是，虽然老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，味觉提示会被避免，因为它会引发条件性厌恶状态的发生（即退出）。鉴于对味觉提示的更大程度的回避（以及更大的厌恶性TR）与更大的药物寻求和吸毒行为有关，因此我们识别潜在的神经回路至关重要。为此，初步数据揭示了一个新的病变部位（丘脑口感觉区，TOA），当与吗啡或可卡因等滥用药物配对时，该部位会选择性地破坏对味觉提示的回避，但与高回报的 1.0 配对时则不会。 M 蔗糖溶液或假定的厌恶剂 LiCl。此外，有证据表明，TOA 可能对于出现药物相关提示后出现提示诱导的戒断反应至关重要。鉴于这些新发现，Specific Aim 1 将使用味觉提示与实验者递送的药物相结合来验证病变位置。此后，特定目标 2 将使用药物自我给药来测试这样的假设：TOA 损伤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吸毒行为。最后，具体目标 3 将测量厌恶 TR 行为以及其他指标，以测试损伤引起的行为中断是否伴随着条件厌恶状态发作的中断。