Prenatal IV nicotine: Long-term vulnerability to stimulant drugs

描述（由申请人提供）：母亲吸烟是美国的一个主要公共卫生问题。总体而言，美国约有20%的女性是常规吸烟者。只有30%的美国女性在发现自己怀孕后戒烟。流行病学研究表明，母亲在整个怀孕期间每天吸烟10支以下的儿童更容易出现药物滥用障碍。目前，人们对产前尼古丁（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。拟议的研究计划将测试的假设，重复，产前IV NIC将改变正常的mesocorticolimbic DA功能在妊娠期间，从而改变运动，加强，并在成年后的奖励METH或COC的影响。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内（IV）甲基苯丙胺（METH）或可卡因（COC）诱导的行为敏化的诱导和表达的剂量依赖性效应。我们已经发现，母亲的烟雾暴露（pueroNIC）产生增加COC诱导的女性后代的多动症。其次，我们将确定成年雄性和雌性大鼠产前暴露于NIC和行为致敏IV METH或COC的DA受体和DA转运蛋白的变化，以建立作用机制。第三，将确定产前NIC对成年雌性和雄性大鼠中IV METH或COC产生的相对强化和奖励的影响。本研究提案的长期计划目标是阐明使子宫内NIC暴露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，与当代方法相结合，以评估药物相关的行为，是创新的，并将转化为药物滥用的健康问题和神经系统并发症，导致母亲吸烟。这项研究的最终目标是制定药物预防战略和药物疗法，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.