SYNAPTIC TRANSMISSION AND SENSITIZATION TO NICOTINE

尼古丁成瘾的因果链始于这种烟草生物碱与 烟碱乙酰胆碱受体（nAChRs）。这种相互作用导致CMS中奖励中心的激活， 包括中脑多巴胺（DA）系统，它最终导致行为强化 和上瘾。我们最近对nAChRs对中脑多巴胺控制的贡献的研究 (DA)神经元兴奋性表明nAChR可以改变对DA神经元的抑制性和兴奋性输入。 通过nAChRs增强兴奋性神经递质传递可以有助于长期的神经递质传递。 这些突触的增强作用。有趣的是，抑制性GABA能传递的调节 双相特征，其中尼古丁引起活动增加然后减少，导致 DA神经元的去抑制。虽然这些对尼古丁急性反应的观察提供了有趣的结果， nAChRs和腹侧被盖区DA神经元兴奋性之间的联系，本提案中的实验将 扩展这些观察结果，以测试尼古丁暴露对nAChR敏感性和功能的影响 在奖励回路中。已知尼古丁暴露会导致nAChR功能上调， 放射性配体结合。此外，尼古丁沿着其他滥用药物可诱导长时程增强 (LTP)多巴胺神经元的兴奋性输入。我们将检验nAChR上调 有助于DA系统及其传入投射内的LTP诱导。利用电生理学 从成年大鼠的脑切片，我们将评估发生在动物的nAChR特性的变化， 暴露于尼古丁的四种方案之一，从1到15天的暴露。治疗方案 强度和持续时间不同，旨在代表尼古丁暴露的范围，模拟 人类接触尼古丁的差异很大。我们预计不同的治疗方案将导致 nAChR功能和放射性配体结合的上调范围。本项目的实验将研究 尼古丁暴露后的功能上调和LTP表达。结果将与数据相关联 从项目1和项目3中进行的行为、生物化学和分子测定。将调查结果与 与我们的合作者将提供新的见解尼古丁诱导的变化，在奖励电路， 最终导致尼古丁成瘾的病因。

The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkyloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CMS, including the mesoaccumbens dopamine (DA) system, which ultimately leads to behavioral reinforcement and addiction. Our recent investigations into the contribution of nAChRs to the control of midbrain dopamine (DA) neuron excitability indicate that nAChRs can modify both inhibitory and excitatory inputs to DA neurons. The enhancement of excitatory glutamatergic transmission by nAChRs can contribute to long-term potentiation of these synapses. Interestingly, the modulation of inhibitory GABAergic transmission has biphasic characteristics, where nicotine causes both an increase and then a decrease in activity, leading to disinhibition of the DA neurons. While these observations on acute responses to nicotine provide interesting connections between nAChRs and the excitability of VTA DA neurons, experiments in this proposal will extend these observations to test the impact of nicotine exposure on the sensitivity and function of nAChRs within the reward circuitry. Nicotine exposure is known to cause upregulation of nAChR function and radioligand binding. In addition, nicotine along with other drugs of abuse can induce long term potentiation (LTP) of the excitatory inputs to DA neurons. We will test the hypothesis that nAChR upregulation contributes to LTP induction within the DA system and its afferent projections. Using electrophysiology in brain slices from adult rats, we will assess the changes in nAChR properties that occur in animals that have been exposed to nicotine in one of four regimens, ranging from one to 15 days of exposure. The regimens vary in intensity and duration and are designed to represent a spectrum of nicotine exposure, mimicking to the wide variation in nicotine exposure seen in humans. We expect that the different regimens will result in a range of upregulation of nAChR function and radioligand binding. Experiments in this project will investigate functional upregulation and LTP expression following nicotine exposure. Results will be correlated with data from behavioral, biochemical, and molecular assays conducted in Projects 1 and 3. Correlating the findings with our collaborators' will provide novel insights into the nicotine-induced changes in reward circuitry that ultimately contribute to the etiology of nicotine addiction.