Cellular and Synaptic Physiology During the Progression to Nicotine Abuse

描述(申请人提供)：尼古丁是烟草的主要成瘾成分，尽管有害，但它仍会促使人们继续使用尼古丁。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44万人死亡和超过750亿美元的直接医疗费用。虽然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刺激药物不当强化的行为方面发挥了至关重要的作用。拟议的研究检验了以下广泛的假设：在从偶尔使用烟草(尼古丁)到成瘾的过程中，DA系统发生了变化，促成了向尼古丁滥用的过渡。这些研究特别研究了随着尼古丁暴露时间的延长而演变的DA系统中的生理变化。DA系统中的变化通常使用通常作为学习和记忆基础的突触可塑性机制。因此，一个辅助假设是尼古丁诱导了与药物相关的记忆背后的那种突触变化。最近的研究表明，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。药物颠覆了正常的记忆机制，导致了随着成瘾的发展而积累的行为的长期变化。随后，唤起与成瘾行为相关的记忆的环境线索会激发渴望和复发。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长期暴露，最后到长期长期暴露。在三个特定的目标中，我们将使用活体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神经元与邻近电路之间的关系。体内测量的DA神经元的放电模式将指导使用微透析法和快速循环伏安法测量尼古丁对DA释放的调节。此外，对于每一次尼古丁暴露，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进程。突触可塑性的时间进程表明，在药物相关记忆改变DA信号的过程中，存在一个脆弱的窗口。我们的策略是研究体内的DA信号，以保护整体完整的生物系统。然后，我们牺牲了体内研究提供的一些相关性，以追求更大的实验控制和更多的细节使用体外脑片。一种应用于多个水平的神经元整合的生理学研究的新组合将提供目前尼古丁成瘾领域缺乏的补充数据集。与公共健康相关的尼古丁成瘾会刺激烟草的使用，在美国每年导致约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，这些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.