Behavioral compensation in goal-directed action: Long term effects of voluntary methamphetamine taking versus passive exposure

目标导向行动中的行为补偿：自愿服用甲基苯丙胺与被动接触甲基苯丙胺的长期影响

• 批准号: 10742559
• 负责人: Charles Lee Pickens
• 金额: $ 7.13万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742559
• 关键词: Affect; American; Amphetamines; Animals; Area; Behavior; Behavioral; Brain; Compensation; Cues; Cytoskeleton; Data; Decision Making; Dose; Drug Exposure; Drug usage; Drug user; Exposure to; Food; Functional disorder; Future; Goals; Human; Impairment; Injections; Intake; Laboratories; Laboratory Animals; Lateral; Learning; Lesion; Light; Literature; Location; Long-Term Effects; Measures; Mental disorders; Methamphetamine; Methamphetamine use disorder; Mission; Modeling; National Institute of Drug Abuse; Nature; Neurobiology; Neuronal Dysfunction; Neurons; Outcome; Performance; Persons; Pharmaceutical Preparations; Process; Proteins; Rattus; Research; Rewards; Rodent; Self Administration; Signal Transduction; Substance Use Disorder; Thalamic structure; Time; Tracer; Training; Variant; Visual; analog; brain dysfunction; drug abuser; drug of abuse; flexibility; improved; methamphetamine exposure; methamphetamine use; nervous system disorder; neural; neural circuit; pharmacologic; preservation; prevent; psychostimulant; response; stimulant exposure; sustained recovery

PROJECT SUMMARY Goals can change over time, and it is important to adapt our actions according to our current goals. There is extensive evidence that long-term drug use can lead to dysfunction of neural circuits involved in goal-directed decision-making. However, decision-making impairments are not always apparent in drug users, possibly because drug-induced malfunction in certain brain areas involved in decision-making causes compensation in which the brain reorganizes and/or different strategies are used to maintain adequate decision-making. This proposal will examine changes in behavioral strategy and alterations in neuronal processing that maintain adequate decision-making when the brain areas that normally support decision-making malfunction due to prior voluntary methamphetamine intake or targeted disruption. The proposed studies will assess rats in a devaluation task in which specific responses and cues predict rewards, and then the value of one of the rewards is decreased. Flexible decision-making that is goal-directed would lead to a decrease in responses for the reward with decreased value. Importantly, in our task, the action that leads to the devalued reward is signaled by a response on a lever in a particular spatial location and with a particular light cue above the lever, although normal rats guide their behavior based on the lever-location. However, decreasing the function of prelimbic cortex (usually required to associate a response in a particular location with a specific reward) does not impair the ability to decrease responses on the lever-light compound associated with that reward. Prior research from our lab suggests that animals compensate for the loss of ability to associate the lever-location with the reward (due to prelimbic cortex lesions) by instead associating the cuelight above the lever with the reward, a type of learning that is supported by orbitofrontal cortex. These prelimbic cortex lesions are associated with an increase in neuronal activity in orbitofrontal cortex and in neuronal activity in mediodorsal thalamus neurons projecting to orbitofrontal cortex during learning. As prior research suggests that psychostimulant exposure can lead to alterations in the function of prelimbic cortex and/or lateral orbitofrontal cortex, I will determine long-term effects of prior methamphetamine self-administration on the neural circuits underlying devaluation and whether compensation between brain areas can preserve intact devaluation behavior. In addition, as prior research suggests that voluntary drug-taking causes different neurobiological and behavioral changes than being passively exposed to drugs, I will compare effects of passive methamphetamine exposure to those of voluntary drug-taking. The proposed research is relevant to one component of NIDA’s mission, to “develop new and improved treatments to help people with substance use disorders achieve and maintain a meaningful and sustained recovery”. Our findings may help to understand how drug users may maintain adequate decision-making after drug-induced brain dysfunction, and may identify alternative behavioral strategies that could improve this decision-making after past drug use.

项目概要 目标会随着时间的推移而改变，根据当前的目标调整我们的行动非常重要。 大量证据表明，长期吸毒会导致参与目标导向的神经回路功能障碍 然而，吸毒者的决策障碍并不总是很明显。 因为药物引起的某些涉及决策的大脑区域的功能障碍会导致代偿 大脑重新组织和/或使用不同的策略来维持适当的决策。 该提案将检查行为策略的变化和神经处理的改变，以维持 当通常支持决策的大脑区域由于以下原因而发生故障时，可以做出适当的决策 拟议的研究将评估大鼠先前的自愿摄入甲基苯丙胺或有针对性的破坏。 贬值任务，其中特定的反应和线索预测奖励，然后预测其中之一的价值 以目标为导向的灵活决策会导致响应减少。 重要的是，在我们的任务中，导致奖励贬值的行动是。 通过特定空间位置的杠杆上的响应以及杠杆上方的特定光提示来发出信号， 尽管正常大鼠根据杠杆位置来指导其行为，但是，降低了杠杆的功能。 前边缘皮层（通常需要将特定位置的响应与特定奖励相关联） 不损害减少与该奖励相关的杠杆光化合物的反应的能力。 我们实验室的研究表明，动物可以弥补关联杠杆位置能力的丧失 通过将杠杆上方的提示灯与奖励（由于前缘皮质损伤）相关联 奖励，一种由眶额皮层支持的学习类型。 与眶额皮层神经元活动和内侧背侧神经元活动的增加有关 正如先前的研究表明，丘脑神经元在学习过程中投射到眶额皮层。 精神兴奋剂暴露可能导致前边缘皮质和/或外侧眶额功能的改变 皮层，我将确定先前自我施用甲基苯丙胺对神经回路的长期影响 潜在的贬值以及大脑区域之间的补偿是否可以保持完整的贬值 此外，先前的研究表明，自愿吸毒会导致不同的神经生物学行为。 和行为改变相比被动接触毒品，我将比较被动接触毒品的影响 甲基苯丙胺暴露与自愿吸毒者的接触情况与一项拟议的研究有关。 NIDA 使命的一部分是“开发新的和改进的治疗方法来帮助药物滥用者 疾病实现并维持有意义和持续的恢复”。我们的研究结果可能有助于理解。 吸毒者在药物引起的脑功能障碍后如何保持充分的决策，并可以识别 可以在过去吸毒后改善这种决策的替代行为策略。