Neurodevelopmental Basis(es) of Nicotine Sensitization

尼古丁致敏的神经发育基础

• 批准号: 6543815
• 负责人: Rosemarie M Booze
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-28 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6543815
• 关键词: autoradiography; behavioral habituation /sensitization; corpus striatum; developmental neurobiology; dopamine receptor; gender difference; hormones; inhibitor /antagonist; intravenous administration; laboratory rat; nicotine; nucleus accumbens; pharmacokinetics; receptor binding

DESCRIPTION (provided by applicant): Gender differences in response to psychostimulants have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to psychostimulants remain for the most part, unexplained. The common observation is that females are more sensitive to psychostimulants, such as nicotine. Our hypothesis is: Gonadal hormones in adulthood and development act on dopaminergic systems, providing the underlying basis for the gender differences in behavioral sensitization produced by repeated IV nicotine administration. First, we will determine whether pharmacokinetic differences between the sexes result in higher levels of nicotine in the female brain. We have successfully developed a technically simple, economical and practical non-tethered technique for repeatedly administering IV nicotine to freely moving, group-housed rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking nicotine levels following IV dosing in rats, which is similar to that observed in humans, as opposed to SC or PO dosing. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of nicotine. Second, we will determine whether gonadal hormones regulate the expression of gender differences in response to nicotine in adulthood. We will test the ability of gonadal hormones to modulate dopamine receptor responsiveness to chronic nicotine administration. Third, we will determine whether the brain organizational (neurodevelopmental) effect of the perinatal hormonal milieu mediates the gender differences in nicotine responsiveness. We have pharmacologically characterized a recently discovered unique dopamine receptor subtype (D3) which is localized to the striatum/nucleus accumbens region of the brain. We hypothesize that alterations in dopaminergic systems underlie the gender differences produced by repeated IV nicotine administration. Our long-term goal is to determine the role of the dopamine neurochemical system in gender differences following repeated IV nicotine administration. The ultimate goal of this research is to develop pharmacological interventions to assist in correcting the behavioral problems associated with chronic tobacco use in humans, and specifically to provide potential insight into effective gender-specific treatment strategies for smoking cessation.

描述（由申请方提供）：动物和人类均报告了对精神兴奋剂反应的性别差异;然而，这些对精神兴奋剂反应的性别差异的生物学机制在很大程度上仍无法解释。普遍的观察结果是，女性对尼古丁等精神兴奋剂更敏感。我们的假设是：成年期和发育期的性腺激素作用于多巴胺能系统，为重复IV尼古丁给药产生的行为致敏性的性别差异提供了基础。首先，我们将确定性别之间的药代动力学差异是否导致女性大脑中尼古丁水平较高。我们成功开发了一种技术简单、经济实用的非栓系技术，用于对自由活动的分组饲养大鼠重复IV给予尼古丁。详细的药代动力学分析表明，大鼠IV给药后尼古丁水平迅速达到峰值，这与在人体中观察到的结果相似，而不是SC或PO给药。使用该临床相关IV啮齿动物给药模型，我们将确定药代动力学因素是否导致雌性动物对尼古丁效应的敏感性增加。其次，我们将确定性腺激素是否调节成年期尼古丁反应的性别差异表达。我们将测试性腺激素调节多巴胺受体对慢性尼古丁给药的反应性的能力。第三，我们将确定围产期激素环境的脑组织（神经发育）效应是否介导尼古丁反应性的性别差异。我们已经确定了最近发现的一种独特的多巴胺受体亚型（D3），它定位于大脑的纹状体/丘脑核区域。我们假设多巴胺能系统的改变是重复IV尼古丁给药产生的性别差异的基础。我们的长期目标是确定重复IV尼古丁给药后多巴胺神经化学系统在性别差异中的作用。这项研究的最终目标是开发药物干预措施，以帮助纠正与人类慢性烟草使用相关的行为问题，特别是为有效的性别特异性戒烟治疗策略提供潜在的见解。