ANIMAL MODELS OF NICOTINE SUSCEPTIBILITY

大多数成年吸烟者是在儿童时期开始吸烟的。以前大多数关于尼古丁生物学效应的研究都集中在成年人身上，而不是青春期。青春期是一个以性成熟和大脑结构和功能发生重大变化为特征的发育时期。在目前的建议中，我们将使用动物模型来检查导致尼古丁易感性的生物学因素。特别是，我们将测试以下假设：(1)尼古丁的强化/厌恶效应的平衡在青少年中比在成年人中更大。(2)尼古丁依赖易感性的个体差异与应激反应的差异有关。提出了三个具体目标。首先，尼古丁的影响将在出生后30天的幼年大鼠和成年大鼠中进行比较。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，将动物斩首并采集躯干血液用于测量皮质酮水平。大脑将被原位杂交处理，用于定量分析特定神经元群体中即时早期基因（cfos） mRNA的表达。实验将在雄性和雌性大鼠中进行，以确定尼古丁对青少年的强化作用是否比成年大鼠更强，同时使用条件位置偏好和自我给药范式。还将对动物进行试验，以确定对尼古丁的运动激活效应的条件致敏在幼年动物身上是否比成年动物发生得更快，并确定幼年动物接触尼古丁是否会增加成年动物对尼古丁的敏感性。第二，应激反应的个体差异将由幼崽出生后两周内被处理(H)或不处理（NH）的过程引起。然后将H和NH组作为幼鼠和成年鼠进行比较，以确定应激反应的差异是否会导致尼古丁对运动、血浆皮质酮和cfos表达的不同急性影响。我们还将研究尼古丁在H组和NH组中强化作用的差异，以及慢性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。将研究尼古丁对C3H和c57b1 / 6j小鼠的急性和慢性影响，以及对特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个体对尼古丁反应差异的生物学机制的重要信息，并将补充项目1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.