Prenatal IV nicotine: Long-term vulnerability to stimulant drugs

描述（由申请人提供）：在美国，母亲吸烟是一个主要的公共卫生问题。总体而言，美国约有20%的女性经常吸烟。在美国，只有30%的吸烟妇女在发现自己怀孕后戒烟。流行病学研究表明，在怀孕期间每天吸烟10支的母亲的孩子更容易出现药物滥用障碍。目前，关于产前尼古丁（NIC）暴露使母亲吸烟者的后代更容易滥用药物的神经行为机制知之甚少。拟议的研究计划将检验一个假设，即重复的产前IV NIC将改变妊娠期间正常的中皮质边缘DA功能，从而改变冰毒或COC在成年期的运动、强化和奖励作用。随后的精神兴奋剂诱导的行为改变的机制是多巴胺能。首先，将确定产前NIC对成年雌性和雄性大鼠静脉注射（IV）甲基苯丙胺（METH）或可卡因（COC）诱导的行为致敏的诱导和表达的剂量依赖性效应。我们发现母亲吸烟暴露（假定为NIC）会增加coc诱导的雌性后代多动症。其次，我们将确定成年雄性和雌性大鼠在产前暴露于NIC和IV甲基安非他明或COC行为致敏时DA受体和DA转运体的变化，以建立其作用机制。第三，确定产前NIC对成年雌性和雄性大鼠静脉注射甲基安非他明或COC产生的相对强化和奖励的影响。本研究计划的长期规划目标是阐明使人在子宫内暴露于NIC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，结合当代评估药物相关行为的方法，是创新的，并将转化为药物滥用的健康问题和母亲吸烟导致的神经系统并发症。本研究的最终目标是制定药物预防策略和药物治疗，以减少对药物滥用的脆弱性。

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.