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

描述(申请人提供)：烟草使用是全球可预防死亡的主要原因。这种习惯不仅让个人吸烟者感到虚弱，而且对他们周围的人(二手烟)也是如此。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，除了它的无条件作用外，尼古丁还具有条件刺激作用，这可能有助于保持吸烟习惯。研究尼古丁作为条件刺激的学习过程是一个与尼古丁依赖相关的研究较少的领域。如果一个目标是开发一种全面的 理论，并因此制定更好的预防和治疗策略。一项评估尼古丁诱发的CR所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的升高揭示)依赖于尼古丁的学习历史。这项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前后轴内的解剖联系并不均匀，它们对条件反射的控制也可能不同，因此将测试dmCPu的前部(a-dmCPu)和后部(p-dmCPu)是否参与尼古丁诱发的CR的获得和表达。本研究将检测a-或p-dmCPu的永久性神经毒素损伤对尼古丁诱导的CR获得的影响，以及a-或p-dmCPu的短暂损伤对尼古丁诱导的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的损毁(NMDA)或假损毁(载体)。在尼古丁CS训练期间(每天共32次)，尼古丁注射(0.4 mg/kg；SC)将100%与间歇性(每次36次)蔗糖注射配对；在替代盐水日将不提供蔗糖。使用这种方案，尼古丁CS很容易获得对目标跟踪CR(预期性觅食反应)的控制。获得这种尼古丁诱发的CR的缺陷(使用该标准方案)将表明一个区域参与了对尼古丁CS的CR的获取。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)，然后接受颅内导管植入(a-或p-dmCPu)。在检测尼古丁诱发的CR之前，大鼠将被双侧注入利多卡因或生理盐水。在检测过程中，CR的减弱将表明受累区域在CR表达中的关键参与。从这些实验中获得的知识将填补在理解区域神经生物学过程方面的空白，这些过程可能有助于烟草依赖的顽固性。

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.