Nicotine Addiction: Influence of Prenatal and Adolescent Exposure

描述(由申请人提供)：尼古丁与吸烟对怀孕和胎儿发育的许多不利影响有关。除了病理生理后果外，流行病学数据表明，在子宫内暴露于烟草烟雾的人成年后更有可能滥用尼古丁。青春期也是尼古丁的脆弱时期。目前，引发和维持尼古丁成瘾的神经生物学因素尚不清楚；这是我们知识基础中的一个严重缺口。我们的初步研究表明，产前暴露于尼古丁会对尼古丁的自我给药和GABA能神经传递相关基因的表达产生长期影响。我们拟议的实验建立在这些发现的基础上，并将产生关于产前和/或青春期尼古丁暴露对成年大鼠尼古丁自我管理的影响的新的和潜在的重要信息。实验1将进一步表征产前尼古丁暴露对成年大鼠尼古丁自我给药的影响。将确定改变成人尼古丁自我给药所需的产前尼古丁阈值剂量，以确定暴露于二手烟的后果。实验2将验证这样一个假设，即与单独的产前暴露相比，产前和青春期联合暴露于尼古丁将导致尼古丁自我给药的更大增加。我们还将发现青春期周围是否是尼古丁易感的关键时期。一个关键的问题是，在发育过程中接触尼古丁是否只会影响对尼古丁的反应。实验3将验证这样的假设，即产前和/或青春期暴露于尼古丁也会增加可卡因的自我给药。实验4将通过评估产前和/或青春期尼古丁暴露引起的GABA能神经传递相关基因的变化，开始阐明尼古丁自我给药增加的机制。相关性：我们的实验将产生关键信息，这些信息可能会影响尼古丁成瘾适当药物治疗和干预策略的开发和实施。此外，研究结果还可能确定当前治疗策略的潜在长期和潜在有害影响。使用尼古丁贴片或尼古丁口香糖治疗孕妇可能会减少她们的吸烟，但会增加她们的后代患上尼古丁成瘾的风险。

DESCRIPTION (provided by applicant): Nicotine is implicated in many of the adverse effects of smoking on pregnancy and fetal development. Besides the pathophysiological consequences, epidemiologic data indicate that individuals exposed to tobacco smoke in utero are more likely to abuse nicotine as adults. Adolescence also is a period of vulnerability to nicotine. Currently, the neurobiological factors underlying the initiation and maintenance of nicotine addiction are not known; this is a critical gap in our knowledge base. Our preliminary studies show that prenatal exposure to nicotine produces long-term effects on nicotine self-administration and the expression of genes related to GABAergic neurotransmission. Our proposed experiments build upon these findings and will generate new and potentially important information on the influence of prenatal and/or adolescent nicotine exposure on nicotine self-administration in the adult rat. Experiment #1 will characterize further the effects of prenatal nicotine exposure on nicotine self-administration in the adult rat. The threshold dose of prenatal nicotine required to alter adult nicotine self-administration will be determined in order to ascertain the consequences of exposure to second-hand smoke. Experiment #2 will test the hypothesis that combined prenatal and peripuberal exposure to nicotine will lead to greater increases in nicotine self- administration, compared to prenatal exposure alone. We also will find whether the peripuberal period is a critical period of vulnerability to nicotine. A critical question is whether exposure to nicotine during development affects only the responses to nicotine. Experiment #3 will test the hypothesis that prenatal and/or peripuberal exposure to nicotine also increases cocaine self-administration. Experiment #4 will begin to elucidate the mechanisms underlying increased nicotine self-administration by evaluating changes in genes related to GABAergic neurotransmission as a consequence of prenatal and/or peripuberal exposure to nicotine. Relevance: Our experiments will yield critical information that might impact the development and implementation of appropriate pharmacologic treatment and intervention strategies for nicotine addiction. In addition, the results may identify potential long-term and potential deleterious effects of current treatment strategies. Using a nicotine patch or nicotine gum to treat pregnant women might reduce their smoking, but increase the vulnerability of their offspring to develop nicotine addiction.