Cellular and Synaptic Physiology During the Progression to Nicotine Abuse

描述（由申请人提供）：尼古丁是烟草的主要成瘾性成分，尽管有有害影响，但仍促使人们继续使用。在发达国家，烟草使用估计是过早死亡的最大单一原因，在美国每年造成约44万人死亡，直接医疗费用超过750亿美元。尽管大脑的许多区域都参与其中，但中脑多巴胺（DA）系统在获得被包括尼古丁在内的精神兴奋剂不当强化的行为中起着至关重要的作用。拟议的研究检验了以下广泛的假设：在从偶然烟草（尼古丁）使用到成瘾的过程中，DA系统发生了变化，促进了向尼古丁滥用的过渡。这些研究专门研究了随着尼古丁暴露持续时间的推移而进化的DA系统的生理变化。DA系统内的变化通常使用突触可塑性机制，而突触可塑性通常是学习和记忆的基础。因此，一个辅助的假设是，尼古丁引起了与药物相关的记忆的突触变化。最近的进展表明，成瘾与通常归因于学习和记忆的突触可塑性有许多共同之处。药物会破坏正常的记忆机制，导致长期的行为变化，这些变化随着成瘾的持续发展而积累。随后，引发与成瘾行为相关的记忆的环境线索激发了渴望和复发。这三个目的是研究尼古丁暴露引起的生理变化，从急性单次给药到短期慢性暴露，最后到长期慢性暴露。在这三个具体目标中，我们将使用体内单位记录来检查尼古丁对DA神经元放电模式的影响，并检查DA神经元与邻近回路之间的关系。体内测量的DA神经元的放电模式将指导使用微透析和快速循环伏安法测量尼古丁对DA释放的调节的详细研究。此外，对于每次尼古丁暴露，我们将跟踪尼古丁诱导的谷氨酸能传入到腹侧被盖区DA神经元的突触增强的时间过程。突触可塑性的时间过程表明，在此期间，DA信号被药物相关记忆改变。我们的策略是在体内研究DA信号，它保留了整个完整的生物系统。然后，我们牺牲了体内研究提供的一些针对性，以追求更大的实验控制和更详细的体外脑切片。在神经元整合的多个层面上应用生理学研究的新组合将提供目前在尼古丁成瘾领域缺乏的补充数据集。对尼古丁的上瘾促使了烟草的使用，在美国，吸烟每年导致大约44万人死亡，直接医疗费用超过750亿美元。这项研究将确定尼古丁引起的短期和长期神经元变化是尼古丁成瘾的基础。

DESCRIPTION (provided by applicant): Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. In developed countries, tobacco use is estimated to be the largest single cause of premature death, causing approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. Although many areas of the brain participate, the midbrain dopamine (DA) systems serve a vital role in the acquisition of behaviors that are inappropriately reinforced by psychostimulant drugs, including nicotine. The proposed studies examine the following broad hypothesis: during the progression from casual tobacco (nicotine) use to addiction the DA systems change, contributing to the transition to nicotine abuse. The studies specifically examine the physiological changes in the DA systems that evolve as the nicotine exposure continues through time. The changes within the DA systems often use the mechanisms of synaptic plasticity that normally underlie learning and memory. Thus, an ancillary hypothesis is that nicotine induces synaptic changes of the kind that underlie drug-linked memory. Recent advances indicate that addiction shares many commonalities with the synaptic plasticity normally attributed to learning and memory. Drugs subvert normal memory mechanisms, leading to long-lasting changes in behavior that accrue with the ongoing progression of addiction. Subsequently, environmental cues that elicit memories linked to addictive behaviors motivate cravings and relapse. The three aims examine the physiological changes induced by nicotine exposure that progresses from an acute single administration to a short-term chronic exposure and, finally, to a long-term chronic exposure. In each of the three specific aims, we will use in vivo unit recordings to examine nicotine-influences over DA neuron firing patterns and to examine the relationship between DA neurons and the neighboring circuitry. The firing patterns of the DA neurons measured in vivo will guide detailed studies of nicotine modulation of DA release measured using microdialysis and fast cyclic voltammetry. In addition, for each nicotine exposure we will follow the time-course for nicotine-induced synaptic potentiation of the glutamatergic afferents onto DA neurons of the ventral tegmental area. The time course of the synaptic plasticity suggests a window of vulnerability during which DA signaling is altered by drug-associated memory. Our strategy is to investigate DA signaling in vivo, which preserves the overall intact biological systems. Then, we sacrifice some of the pertinence provided by the in vivo studies to pursue greater experimental control and greater detail using in vitro brain slices. A novel combination of physiological studies applied at multiple levels of neuronal integration will provide complementary data sets that are presently lacking within the field of nicotine addiction. PUBLIC HEALTH RELEVANCE Addiction to nicotine motivates tobacco use, which causes approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. This study will determine the nicotine induced short-term and long-term neuronal changes that underlie nicotine addiction.