Nicotine-induced synaptic plasticity in midbrain dopamine neurons

描述(由申请人提供)：有证据表明，大脑中几个已知的调节奖赏信号的区域的突触功能发生了长期和短期的变化。一种类型的变化发生在中脑的多巴胺(DA)神经元中。已有研究表明，单一的急性尼古丁暴露会导致介导诱发突触传递的离子型谷氨酸受体的亚型发生变化。这种转变表现为AMPA/NMDA受体比率的增加。这种增加被认为与突触后AMPA型受体的插入有关，该受体是长时程增强(LTP)的基础。初步数据显示，在幼年(出生后21-35d)C57小鼠中，一次腹腔注射尼古丁可导致中脑DA神经元诱发的谷氨酸电流的AMPA/NMDA受体比率增加。同样的效果也出现在老年(出生后60-90天)小鼠身上，但剂量-反应关系向右移动。这表明，尽管尼古丁仍然能够产生通常与学习和记忆的细胞模型(即LTP)相关的那种突触可塑性，但这种效应的效力随着年龄的增长而减弱。据预测，在较年轻的动物中，这种类型的可塑性对较低剂量的尼古丁更敏感，这种相对敏感性可能导致青少年对尼古丁成瘾的易感性增加。此外，这项建议概述了一系列实验，以确定在这一关键发育时期暴露于尼古丁的影响，并确定年轻时先前暴露于尼古丁是否会降低尼古丁诱导可塑性的剂量阈值。 公共卫生相关性：在美国和世界各地，与吸烟相关的疾病是可预防的死亡的主要原因。尽管有大量关于烟草使用的健康风险的信息，但许多人仍在吸烟，这证明了尼古丁的成瘾作用。旨在阐明尼古丁成瘾机制的研究可能有助于开发有效的方法来预防和治疗最终危及生命的行为。

DESCRIPTION (provided by applicant): There is evidence for both long and short-term changes in synaptic function in several areas of the brain known to mediate reward signals. One type of change occurs in dopamine (DA) neurons of the midbrain. It has been shown that a single, acute exposure to nicotine produces a shift in the subtypes of ionotropic glutamate receptors mediating evoked synaptic transmission. This shift is manifested as an increase in the AMPA/NMDA receptor ratio. This increase is thought to be related to the insertion of postsynaptic AMPA-type receptors that is known to underlie long-term potentiation (LTP). Preliminary data show that in young (21 - 35 postnatal day) C57 mice, a single intraperitoneal injection of nicotine causes an increase in the AMPA/NMDA receptor ratio of evoked glutamate currents in putative midbrain DA neurons. The same effect is also seen in older (60 - 90 postnatal day) mice but with a rightward shift in the dose-response relationship. This suggests that while nicotine is still able to produce the kind of synaptic plasticity that is commonly associated with cellular models of learning and memory (i.e., LTP), the potency of the effect is decreased with age. It is predicted that in younger animals, this type of plasticity will be more sensitive to lower doses of nicotine, and that this relative sensitivity may contribute to the increased vulnerability of adolescents to nicotine addiction. Furthermore, this proposal outlines a course of experiments to determine the effects of exposure to nicotine during this critical developmental period, and to determine if prior exposure to nicotine at a young age lowers the dose threshold for nicotine induced plasticity. PUBLIC HEALTH RELEVANCE: Smoking-related diseases are a major cause of preventable death in the U.S. and around the world. Despite the wealth of information regarding the health risks of tobacco use, many continue to smoke, attesting to the addictive power of nicotine. Research designed to illuminate the mechanisms of nicotine addiction may help in the development of effective methods of prevention and treatment of what is ultimately a life-threatening behavior.