SYNAPTIC TRANSMISSION AND SENSITIZATION TO NICOTINE

尼古丁成瘾的因果链条始于这种烟草醇类物质与烟草的相互作用。 烟碱型乙酰胆碱受体(NAChRs)。该交互作用导致激活CMS中的奖励中心， 包括中隔伏核的多巴胺(DA)系统，这最终导致行为强化 还有毒瘾。我们最近对nAChRs在控制中脑多巴胺中的作用的研究 (DA)神经元兴奋性表明nAChRs可以改变对DA神经元的抑制性和兴奋性输入。 NAChRs增强兴奋性谷氨酸能传递有助于长期 这些突触的增强。有趣的是，抑制GABA能传递的调制 双相特征，其中尼古丁导致活动增加，然后又减少，导致 去抑制多巴胺能神经元。虽然这些关于尼古丁急性反应的观察提供了有趣的 NAChRs和VTA DA神经元的兴奋性之间的联系，这项提议中的实验将 扩展这些观察以测试尼古丁暴露对nAChRs敏感性和功能的影响 在奖赏回路中。已知尼古丁暴露会导致nAChR功能上调和 放射性配基结合。此外，尼古丁与其他滥用药物一起可诱导长时程增强。 (LTP)对DA神经元的兴奋性输入。我们将检验nAChR上调的假设 在DA系统及其传入投射中有助于LTP的诱导。将电生理学应用于 成年大鼠的脑切片，我们将评估nAChR特性的变化，这些变化发生在 曾以四种方案中的一种接触尼古丁，接触时间从一天到15天不等。养生法 在强度和持续时间上不同，旨在代表尼古丁暴露的光谱，模仿 尼古丁暴露在人类身上的差异很大。我们预计不同的方案将导致 NAChR功能上调和放射性配基结合的范围。这个项目中的实验将研究 尼古丁暴露后功能上调和LTP表达。结果将与数据相关联 来自项目1和3中进行的行为、生化和分子分析。 将为尼古丁引起的奖赏回路的变化提供新的见解 最终导致尼古丁成瘾的病因学。

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.