Drug Abuse Vulnerability: Role of Development and Gender

描述（由申请人提供）：发育史和性别被认为是药物成瘾的关键介导因素，影响初始药物使用、滥用升级和复发。发育损伤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压力源和厌恶刺激的反应的系统，从而间接影响药物使用。关于易成瘾性，一个未充分研究的发育损害是产前和产后早期接触和戒断滥用药物。这与发育中的阿片类药物暴露特别相关。药物滥用治疗中心建议阿片类药物依赖的孕妇在整个怀孕期间保持阿片类药物替代治疗，以尽量减少与海洛因使用相关的母亲和胎儿的健康风险。除了阿片类药物的直接作用外，新生儿还会出现长时间的、应激性的阿片类药物戒断（戒断综合征），这可能进一步成为一种发育损伤。许多已发表的研究报告说，性别影响的长期后果的发展侮辱和初步研究表明，性别差异影响的后果产前阿片类药物暴露的措施，成人焦虑行为和疼痛敏感性。然而，还没有一个系统的研究如何产前药物暴露和伴随的压力，出生后阿片类药物戒断，与性别相互作用，影响成年后的滥用倾向，本研究建议的目标。受试者将来自在繁殖前一个月依赖长效合成阿片剂的雌性大鼠，通过分娩进行治疗。出生后，幼崽将被寄养给未接触过毒品的母亲，并接受阿片类药物戒断治疗。在成年期，研究将确定是否产前阿片暴露的雄性和雌性大鼠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;阿片戒断增强焦虑、疼痛敏感性和位置厌恶;以及可卡因和海洛因自我给药的获得和线索诱导的恢复增加。

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.