Role of dmCPu in acquisition and expression of nicotine CS evoked CR

dmCPu 在尼古丁 CS 诱发 CR 的获得和表达中的作用

• 批准号: 8521001
• 负责人: Sergios Charntikov
• 金额: $ 3.66万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-19 至 2015-03-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521001
• 关键词: Absence of pain sensation; Alcohols; Anterior; Applications Grants; Area; Attenuated; Behavior Therapy; Behavioral; Cannulas; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Complex; Conditioned Stimulus; Corpus striatum structure; Dorsal; Environment; Environmental Tobacco Smoke; FOS gene; Food; Food Interactions; Goals; Grant; Habits; Health Expenditures; Individual; Injection of therapeutic agent; Investigation; Knowledge; Learning; Lesion; Lidocaine; Literature; N-Methylaspartate; Neurobiology; Neurotoxins; Nicotine; Nicotine Dependence; Outcome; Pharmacological Treatment; Pharyngeal structure; Physicians; Prevention strategy; Process; Property; Protocols documentation; Rattus; Recording of previous events; Relapse; Reporting; Research; Rewards; Role; Saline; Series; Smell Perception; Smoker; Smoking; Stimulus; Sucrose; Testing; Time; Tobacco; Tobacco Dependence; Tobacco use; Training; United States; Work; addiction; base; conditioning; design; drug craving; economic impact; experience; implantation; interest; irritation; neurobiological mechanism; paired stimuli; peer; productivity loss; public health relevance; putamen; reinforcer; research study; response; theories; treatment strategy

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a powerful stimulant and reinforcer. Importantly, besides its unconditional effects, nicotin also has conditional stimulus effects that may contribute to the tenacity of the smoking habit. Investigation of learning processes involving nicotine as a conditioned stimulus (CS) is an understudied area relevant to nicotine dependence. Understanding these associative processes with the interoceptive effects of nicotine is of importance if a goal is to develop a comprehensive theory of addiction and, hence, develop better prevention and treatment strategies. A preliminary study assessing neurobiological loci involved in nicotine-evoked CR found that activation (as revealed through elevation of c-Fos) of dmCPu was dependent on learning history with nicotine. The proposed research builds on this finding and is designed to elucidate functional involvement of dmCPu in the conditioning processes with nicotine as a CS. Because anatomical connections within anterior-posterior axis of the rat's dorsal striatum are not homogeneous and can differ in their control of conditioning processes, both anterior (a-dmCPu) and posterior (p-dmCPu) portions of dmCPu will be tested for their involvement in acquisition and expression of the nicotine-evoked CR. The current study will examine the effect of permanent neurotoxin lesions of either a- or p-dmCPu on acquisition of nicotine evoked CR, and the effect of transient lesions of either a- or p-dmCPu on the expression of the nicotine-evoked CR. In the first experiment, rats will receive lesions (NMDA) or sham lesions (vehicle) of either a-dmCPu or p-dmCPu before nicotine CS training. During nicotine CS training (32 total daily sessions), nicotine injections (0.4 mg/kg; SC) will be paired 100% of a time with intermittent (36 per session) sucrose deliveries; sucrose will not be available on alternative saline days. Using this protocol, the nicotine CS readily acquires control of a goal-tracking CR (anticipatory food-seeking response). Deficits in acquiring this nicotine- evoked CR (using this standard protocol) will indicate a region's involvement in acquisition of the CR to the nicotine CS. In the second experiment, rats will first undergo nicotine CS training (identical to Experiment 1) and then receive implantation of intracranial cannulae (a- or p-dmCPu). Rats will be bilaterally infused with either lidocaine or saline before testing for the nicotine-evoked CR. Attenuated CR during testing will indicate critical involvement of implicated area in the expression of the CR. Knowledge gained from these experiments will fill a gap in understanding regional neurobiological processes potentially contributing to the tenacity of tobacco dependence.

描述（由申请人提供）：烟草使用是全球可预防死亡的主要原因。这种习惯不仅对个人使用者，而且对他们周围的人（二手烟）都是有害的。尼古丁是烟草制品的主要成瘾成分，是一种强有力的兴奋剂和兴奋剂。重要的是，除了其无条件的影响，尼古丁也有条件的刺激作用，可能有助于顽固的吸烟习惯。研究尼古丁作为条件刺激（CS）的学习过程是一个与尼古丁依赖相关的研究不足的领域。如果目标是开发一种全面的尼古丁治疗方法，那么了解这些与尼古丁内感受性作用相关的过程是重要的。 因此，我们需要制定更好的预防和治疗策略。一项评估尼古丁诱发的CR中涉及的神经生物学位点的初步研究发现，dmCPu的激活（通过c-Fos升高显示）依赖于尼古丁的学习史。拟议的研究建立在这一发现的基础上，旨在阐明dmCPu在尼古丁作为CS的条件反射过程中的功能参与。由于大鼠背侧纹状体的前后轴内的解剖学连接是不均匀的，并且在它们对条件反射过程的控制方面可能不同，因此将测试dmCPu的前部（a-dmCPu）和后部（p-dmCPu）部分是否参与尼古丁诱发的CR的获得和表达。本研究将检查a-或p-dmCPu的永久性神经毒素损伤对尼古丁诱发的CR获得的影响，以及a-或p-dmCPu的暂时性损伤对尼古丁诱发的CR表达的影响。在第一个实验中，大鼠将在尼古丁CS训练之前接受a-dmCPu或p-dmCPu的损伤（NMDA）或假损伤（媒介物）。在尼古丁CS训练期间（每天总共32次），尼古丁注射（0.4 mg/kg; SC）将与间歇性（每次36次）蔗糖输注100%配对;在替代盐水日不提供蔗糖。使用该方案，尼古丁CS容易获得对目标跟踪CR（预期食物寻求反应）的控制。在获取该尼古丁诱发的CR（使用该标准方案）方面的缺陷将指示区域参与到尼古丁CS的CR的获取中。在第二个实验中，大鼠将首先接受尼古丁CS训练（与实验1相同），然后植入颅内插管（a-或p-dmCPu）。在测试尼古丁诱发的CR之前，将向大鼠双侧输注利多卡因或生理盐水。在测试期间减弱的CR将指示在CR表达中涉及的区域的关键参与。从这些实验中获得的知识将填补理解区域神经生物学过程的空白，可能有助于烟草依赖的坚韧性。