Prenatal IV nicotine: Long-term vulnerability to stimulant drugs

描述(申请人提供)：在美国，母亲吸烟是一个主要的公共健康问题。总体而言，美国约20%的女性是经常吸烟的人。只有30%的滥用烟草的美国女性在发现自己怀孕后戒烟。流行病学研究表明，母亲在整个妊娠期每天抽10支烟的孩子更容易患上药物滥用障碍。目前，关于产前尼古丁(NIC)暴露使母亲吸烟者的后代更容易受到药物滥用的神经行为机制知之甚少。拟议的研究计划将检验一种假设，即重复的产前静脉注射NIC将改变妊娠期间正常的中皮质边缘DA功能，从而改变成年后冰毒或COC的运动、增强和奖励效应。精神刺激剂引起的行为改变的机制是多巴胺能。首先，将确定产前NIC对静脉注射甲基苯丙胺(METH)或可卡因(COC)诱导的成年雌性和雄性大鼠行为敏化的诱导和表达的剂量依赖效应。我们发现，母亲吸烟(可能是NIC)导致雌性后代COC诱导的多动增加。其次，我们将测定成年雄性和雌性大鼠产前暴露于NIC和IVM或COC行为致敏后DA受体和DA转运体的变化，以建立其作用机制。第三，将测定产前NIC对成年雌性和雄性大鼠静脉注射冰毒或COC产生的相对强化和奖赏的影响。本研究提案的长期规划目标是阐明在子宫内暴露于NIC的人更容易受到药物滥用的神经生物学机制。产前NIC暴露的IV模型，与评估与药物相关的行为的现代方法相结合，是创新的，将转化为药物滥用的健康问题和母亲吸烟导致的神经并发症。这项研究的最终目标是开发药物预防策略和药物疗法，以减少对药物滥用的易感性。

DESCRIPTION (provided by applicant): Maternal cigarette smoking is a major public health problem in the United States. Overall, approximately 20% of women in the US are regular cigarette smokers. Only 30% of US women who abuse tobacco quit smoking when they find out they are pregnant. Epidemiological studies indicate that children of mothers who smoke -10 cigarettes a day throughout gestation exhibit increased vulnerability for substance abuse disorder. Currently, little is known about the neurobehavioral mechanisms through which prenatal nicotine (NIC) exposure renders offspring of maternal smokers more vulnerable to substance abuse. The proposed program of research will test the hypothesis that repeated, prenatal IV NIC will alter normal mesocorticolimbic DA function during gestation, thereby altering the locomotor, reinforcing, and rewarding effects of METH or COC in adulthood. The proposed mechanism of subsequent psychostimulant-induced behavioral alterations is dopaminergic. First, the dose dependent effects of prenatal NIC on the induction, and expression, of intravenous (IV) methamphetamine (METH) or cocaine (COC)-induced behavioral sensitization in adult female and male rats will be determined. We have found that maternal smoke exposure (putatively NIC) produced increased COC-induced hyperactivity in female offspring. Second, we will determine the changes in DA receptors and DA transporters in adult male and female rats prenatally exposed to NIC and behaviorally sensitized to IV METH or COC to establish a mechanism of action. Third, the effects of prenatal NIC on the relative reinforcement and reward produced by IV METH or COC in adult female and male rats will be determined. The long-term programmatic goal of the present research proposal is to elucidate the neurobiological mechanisms that render people exposed to in utero NIC more vulnerable to substance abuse. The IV model of prenatal NIC exposure, in combination with contemporary methods to assess drug related behaviors, is innovative and will be translational to the health issues of drug abuse and the neurological complications that result from maternal smoking. The ultimate goal of this research is to develop drug prevention strategies and pharmacotherapies to decrease vulnerability to drug abuse.