Drug Abuse Vulnerability: Role of Development and Gender

描述(由申请人提供)：发展史和性别被认为是药物成瘾的关键中介因素，影响最初的药物使用，升级为滥用和复发。发育性侮辱可以影响直接参与药物强化特性的结构和神经化学元素，或者它们可以扰乱调节对应激源和厌恶刺激的反应的系统，从而间接影响药物使用。关于成瘾的脆弱性，一种未被研究的发育侮辱是产前和出生后早期接触和戒除滥用药物。这与发育性阿片类药物的暴露特别相关。药物滥用治疗中心建议阿片依赖孕妇在整个怀孕期间继续接受阿片类药物替代治疗，以最大限度地减少与海洛因使用有关的母亲和胎儿的健康风险。除了鸦片类药物的直接影响外，新生儿还会长期有压力地戒断鸦片类药物(禁欲综合症)，这可能进一步成为对发育的侮辱。许多已发表的研究报道了性别影响发育侮辱的长期后果，初步研究表明，性别对产前阿片类药物暴露对成人焦虑行为和疼痛敏感性的影响存在差异。然而，关于产前药物暴露和出生后阿片类药物戒断的伴随压力如何与性别交互作用影响成年后滥用倾向的系统研究，这是本研究建议的目标。受试者将来自雌性大鼠，雌性大鼠在繁殖前一个月依赖一种长效合成鸦片药，通过分娩进行治疗。出生后，幼崽将被养育到毒品天真的母亲那里，并接受阿片类药物的戒断。在成年期，研究将确定产前暴露于阿片类药物的雄性和雌性大鼠是否对药物诱导的下丘脑-垂体-肾上腺轴的激活和适应具有不同的敏感性；阿片类药物的戒断增加焦虑、疼痛敏感性和地点厌恶；以及增加获得和线索诱导的可卡因和海洛因自我给药的恢复。

DESCRIPTION (provided by applicant): Developmental history and gender are thought to be key mediating factors in drug addiction, affecting initial drug use, escalation to abuse, and relapse. Developmental insults can affect structural and neurochemical elements that are directly involved in the reinforcing properties of drugs, or they can perturb systems that modulate the response to stressors and aversive stimuli and thus, indirectly affect drug use. With respect to addiction vulnerability, an understudied developmental insult is prenatal and early postnatal exposure to and withdrawal from drugs of abuse. This is particularly relevant for developmental opiate exposure. The Center for Substance Abuse Treatment recommends that opiate-dependent pregnant women be maintained on opiate substitution therapy throughout pregnancy to minimize the health risks to the mother and fetus that are associated with heroin use. In addition to the direct effects of opiate, a prolonged and stressful withdrawal from the opiates occurs in the neonate (abstinence syndrome), which can further act as a developmental insult. Numerous published studies have reported that gender influences the long-term consequences of developmental insults and preliminary studies have revealed that gender differentially affects the consequences of prenatal opiate exposure on measures of adult anxiety behavior and pain sensitivity. However, there has not been a systematic study of how prenatal drug exposure and the accompanying stress of postnatal opiate withdrawal, interact with gender to affect abuse liability in adulthood, the goal of this research proposal. Subjects will originate from female rats that are made dependent on a long-acting synthetic opiate one month prior to breeding, with treatment through parturition. After birth the pups will be fostered to drug-naive mothers and undergo opiate withdrawal. In adulthood, studies will determine if prenatal opiate exposed male and female rats have differential sensitivity to drug-induced activation and adaptation of the hypothalamic-pituitary-adrenal axis; opiate-withdrawal enhanced anxiety, pain sensitivity, and place aversion; and increased acquisition and cue-induced reinstatement of cocaine and heroin self-administration.