Neurodevelopmental Basis(es) of Nicotine Sensitization

描述(由申请人提供)：动物和人类对精神刺激剂反应的性别差异已有报道；然而，这些性别差异背后的生物机制在很大程度上仍然没有解释。通常的观察是，女性对尼古丁等精神刺激剂更敏感。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，为重复静脉注射尼古丁所产生的行为敏化的性别差异提供了潜在的基础。首先，我们将确定性别之间的药代动力学差异是否会导致女性大脑中尼古丁水平更高。我们已经成功地开发出一种技术简单、经济实用的非拴系技术，可以重复给自由活动的群养大鼠静脉注射尼古丁。详细的药代动力学分析表明，大鼠静脉注射尼古丁后尼古丁水平迅速达到峰值，这与在人类身上观察到的类似，而不是SC或PO剂量。利用这个临床上相关的静脉注射给药模型，我们将确定药代动力学因素是否有助于增加雌性动物对尼古丁影响的敏感性。其次，我们将确定性腺激素是否调节成年后尼古丁对性别差异的表达。我们将测试性腺激素调节多巴胺受体对长期服用尼古丁的反应的能力。第三，我们将确定围产期激素环境的大脑组织(神经发育)效应是否中介尼古丁反应的性别差异。我们最近发现了一种独特的多巴胺受体亚型(D3)，它定位于大脑的纹状体/伏隔核区域。我们假设，多巴胺能系统的改变是重复静脉注射尼古丁所产生的性别差异的基础。我们的长期目标是确定反复静脉注射尼古丁后，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，以帮助纠正与人类长期使用烟草有关的行为问题，特别是为有效的针对性别的戒烟治疗策略提供潜在的洞察力。

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.