ANIMAL MODELS OF NICOTINE SUSCEPTIBILITY

大多数成年吸烟者在孩提时代就开始吸烟。之前对尼古丁生物效应的大多数研究都集中在成年人身上，而不是青春期，青春期的特点是性成熟，大脑结构和功能发生重大变化。在目前的提案中，我们将使用动物模型来研究尼古丁易感性背后的生物因素。特别是，我们将检验以下假设：(L)尼古丁的增强/厌恶效应在青少年中的平衡比在成年人中更大。(2)尼古丁依赖敏感度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，我们将比较尼古丁对出生后30天的幼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，动物将被斩首，并采集躯干血液以测量皮质酮水平。大脑将通过原位杂交进行处理，以定量分析特定神经元群体中即刻早期基因CFOS的mRNA表达。实验将在雄性和雌性大鼠身上进行，以确定尼古丁在青少年中是否比成年大鼠更强，使用条件位置偏好和自我管理范式。还将对动物进行测试，以确定青少年对尼古丁的运动激活效应的条件性敏感化是否比成年人更快，并确定青少年接触尼古丁是否会增加成年人对尼古丁的敏感性。其次，幼崽在出生后两周内要么被处理(H)，要么不被处理(NH)，这将导致应激反应的个体差异。然后将H组和NH组作为青少年和成人进行比较，以确定压力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。还将检查H组和NH组尼古丁强化效果的差异，以及慢性尼古丁治疗后戒断严重程度的差异。第三，将研究尼古丁对遗传不同品系小鼠的影响。尼古丁对C3H和C57B1/6J小鼠的急性和慢性影响，以及在选定基因改变的转基因小鼠中的影响，都将被检测。这些研究将提供关于个体对尼古丁响应性差异的生物学机制的关键信息，并将补充项目I和2中的人类研究。

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.