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: 8642529
• 负责人: Sergios Charntikov
• 金额: $ 3.7万
• 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/8642529
• 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。这种习惯不仅使个人用户，而且对周围的人（二手吸烟）也使人衰弱。尼古丁是烟草产品的主要成瘾成分，是一种强大的兴奋剂和增强剂。重要的是，除了其无条件的影响外，烟素还具有有条件的刺激作用，可能有助于吸烟习惯的坚韧。研究涉及尼古丁作为条件刺激（CS）的学习过程是与尼古丁依赖性相关的研究领域。如果一个目标是发展一个全面 成瘾理论，因此，发展了更好的预防和治疗策略。一项评估与尼古丁诱发的CR有关的神经生物学基因座的初步研究发现，DMCPU的激活（通过C-FOS的升高表明）取决于使用尼古丁的学习史。拟议的研究基于这一发现，旨在阐明DMCPU在尼古丁作为CS的调理过程中的功能参与。因为大鼠背纹状体前后轴内的解剖连接并不均匀，并且在调节过程的控制方面可能会有所不同，因此将测试DMCPU的前（A-DMCPU）和后验（A-DMCPU）部分（P-DMCPU）部分，以涉及其参与默认和表达的烟丝和表达。当前的研究将研究A-或P-DMCPU永久神经毒素病变对获得尼古丁引起的CR的影响，以及A-或P-DMCPU的瞬时病变对尼古丁诱发的CR的表达的影响。在第一个实验中，在尼古丁CS训练之前，大鼠将接受A-DMCPU或P-DMCPU的病变（NMDA）或假病变（车辆）。在尼古丁CS培训（每日总共32次）中，尼古丁注射（0.4 mg/kg; SC）将与间歇性（每节36次）蔗糖交付的时间搭配100％；在替代盐水时代，蔗糖将不可用。使用此方案，Nicotine CS很容易获得对目标跟踪CR的控制（预期的寻求食物反应）。获取这种尼古丁引起的CR（使用此标准协议）的缺陷将表明该地区参与CR纳入尼古丁CS的介入。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），然后接受颅内插管（A-或P-DMCPU）的植入。在测试尼古丁诱发的Cr之前，将在双侧注入利多卡因或盐水。测试过程中的CR衰减将表明与CR表达中有关区域的至关重要。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，这可能导致烟草依赖性的坚韧性。