ANIMAL MODELS OF NICOTINE SUSCEPTIBILITY

大多数成年吸烟者在儿童时期就开始吸烟。之前大多数关于尼古丁生物效应的研究都集中在成年人而不是青春期，这是一个以性成熟和大脑结构和功能显着变化为特征的发育时期。在本提案中，我们将使用动物模型来检查尼古丁敏感性的生物因素。特别是，我们将测试以下假设：（l）尼古丁的增强/厌恶作用的平衡在青少年中比在成人中更大。 (2) 对尼古丁依赖的易感性的个体差异与压力反应性的变化有关。提出了三个具体目标。 首先，将比较尼古丁对出生后 (p) 30 天的幼年大鼠和成年大鼠的影响。动物将接受尼古丁治疗并进行行为测试。在一些实验结束时，将动物斩首并收集躯干血液以测量皮质酮水平。将通过原位杂交对大脑进行处理，以定量分析特定神经元群体中即早期基因 cfos 的 mRNA 表达。将对雄性和雌性大鼠进行实验，以使用条件性位置偏好和自我给药范例来确定尼古丁在青少年中是否比成人更增强。还将对动物进行测试，以确定青少年对尼古丁运动激活作用的条件性过敏是否比成人更快发生，并确定青少年接触尼古丁是否会增加成人对尼古丁的敏感性。其次，应激反应的个体差异将由出生后两周内被触摸（H）或不被触摸（NH）的过程引起。 然后将 H 组和 NH 组作为青少年和成人进行比较，以确定应激反应性的差异是否导致尼古丁对运动、血浆皮质酮和 cfos 表达的不同急性影响。还将检查 H 组和 NH 组中尼古丁增强作用的差异，以及长期尼古丁治疗后戒断严重程度的差异。第三，将研究尼古丁对基因不同的小鼠品系的影响。将检查尼古丁对 C3H 和 C57B1/6J 小鼠以及选定基因发生改变的转基因小鼠的急性和慢性影响。这些研究将提供关于尼古丁反应个体差异背后的生物机制的关键信息，并将补充项目 I 和 2 中的人体研究。

The majority of adult smokers initiate smoking as children. Most previous studies of the biological effects of nicotine have focused on adults rather on adolescence, a developmental period that is characterized by sexual maturation and by significant changes in brain structure and function. In the present proposal we will use animal models to examine the biological factors that underlie susceptibility to nicotine. In particular, we will test the following hypotheses: (l) That the balance of reinforcing/aversive effects of nicotine is greater in juveniles than in adults. (2) That individual differences in susceptibility to nicotine dependence are associated with variations in stress responsivity. Three specific aims are proposed. First, the effects of nicotine will be compared in juvenile rats aged postnatal day (p) 30 and in adults. Animals will be treated with nicotine and tested behaviorally. At the end Of some experiments animals will be decapitated and trunk blood collected for the measurement of corticosterone levels. Brains will be processed by in situ hybridization for quantitative analysis of the expression of mRNA for the immediate early gene, cfos, in specific neuronal populations. Experiments will be conducted with both male and female rats to determine whether nicotine is more reinforcing in juveniles than adults using both conditioned place preference and self adrnistration paradigms. Animals will also be tested to determine whether conditioned sensitization to the locomotor activating effects of nicotine Occurs more rapidly in juveniles than adults, and to determine whether juvenile exposure to nicotine increases sensitivity to nicotine in adults. Second, individual differences in stress responsivity will be induced by a procedure in which pups are either handled (H) or not handled (NH) for two weeks after birth. H and NH groups will then be compared as juveniles and adults to determine whether differences in stress responsivity result in different acute effects of nicotine on locomotion, plasma corticosterone and cfos expression. Differences in the reinforcing effects of nicotine in H and NH groups will also be examined, as will differences in withdrawal severity following chronic nicotine treatment. Third, the effects of nicotine on genetically distinct strains of mice will be studied. Both acute and chronic effects of nicotine in C3H andC57B1/6J mice, and in transgenic mice with alterations in selected genes, will be examined. These studies will provide critical information on the biological mechanisms underlying individual variations in responsivity to nicotine and will complement the human studies in projects I and 2.