Protective benefits of maternal behavior on susceptibility for drug abuse

描述（由申请人提供）：年轻女性滥用药物的情况正在上升，最近的一份报告指出，在12-17岁的可卡因使用者中，56%是女性。与男性相比，女性在吸毒成瘾的各个阶段升级得更快，这使她们特别容易受到可卡因的有害影响。对男性有效的可卡因滥用药物治疗，如纳曲酮，对女性无效，甚至会增加吸毒。虽然有可能针对妇女可卡因滥用制定针对性别的药物治疗，但也需要非药物治疗。对实验动物的研究和对人类的调查研究表明，在药物滥用方面形成牢固的社会关系具有潜在的保护作用。老鼠形成的最牢固的社会关系是母子关系。即使在后代断奶后，雌性大鼠的学习和记忆能力也有所提高，探索和觅食能力有所增强，认知功能的年龄相关性下降有所减弱，神经行为应激和恐惧反应也有所减少。这些有益的改变在后代离开巢穴后会持续数月，这表明相对永久性的神经重组。重要的是，这些母性行为的好处发生在未生育的养母和被诱导为母性行为的雄性身上，这表明这些好处并不需要怀孕和分娩。滥用药物和社会纽带的形成都会引起中边缘多巴胺通路神经元靶点的变化，特别是在伏隔核和纹状体。当对同种或滥用药物的依恋被诱导时，该神经系统形成对替代目标的依恋的能力就会降低。因此，与雌性配对的雄性草原田鼠不会对低剂量的安非他命产生条件偏好，而没有配对的雄性则会。同样，表现出对安非他明敏感的雄性田鼠在与雌性田鼠接触时也不容易形成配对关系。我们实验室的初步数据表明，与未分娩的同龄雌性相比，初产雌性在重复施用可卡因时表现出较少的行为敏感性。本文提出的实验将检验一个假设，即在母亲照顾孩子的过程中（无论女性是否为产妇），社会纽带的形成可以保护女性免受药物滥用的影响。具体来说，实验将通过行为致敏范式和体内微透析来检验照顾幼鼠是否会影响可卡因自我给药行为（即获取速率、自我给药动机、非强化期间的持续反应、面对不良结果时的持续服药），和/或动物对重复可卡因暴露的内源性反应。

DESCRIPTION (provided by applicant): Drug abuse among young women is on the rise, with a recent report stating that 56 percent of cocaine users ages 12-17 are women. Women escalate more rapidly through all stages of drug addiction as compared to men, making them especially vulnerable to the deleterious effects of cocaine. Pharmacological treatments for cocaine abuse that are effective in men, such as naltrexone, are ineffective in females or even increase drug use. While it may be possible to develop gender-specific pharmacologic treatments for cocaine abuse in women, non-pharmacologic treatments are also needed. Research in laboratory animals and survey research with humans has indicated a potentially protective effect of the formation of strong social bonds with regards to drug abuse. The strongest social bond formed in rats is the mother-infant bond. Following the rearing of offspring, female rats demonstrate improved learning and memory, increased exploration and foraging ability, attenuated age-related decreases in cognitive function, and decreased neurobehavioral stress and fear responses, even after the offspring have been weaned. These beneficial alterations have been shown to persist for months after the offspring have left the nest, indicating relatively permanent neural reorganization. Importantly, these benefits of maternal behavior occur in nulliparous foster mothers and males that have been induced to act maternally, indicating that pregnancy and parturition are not required for these benefits to be seen. Both drugs of abuse and formation of social bonds induce changes in the neuronal targets of the mesolimbic dopamine pathway, in particular in the nucleus accumbens and striatum. When attachment to a conspecific or drug of abuse is induced, the ability of this neural system to form an attachment to alternate goals is reduced. So, male prairie voles that have pair-bonded with a female do not develop a conditioned place preference to a low dose of amphetamine, while non-bonded males do. Likewise, male voles that have exhibited sensitization to amphetamine do not readily form a pair-bond when presented with a female. Preliminary data from our laboratory have shown that primiparous females exhibit less behavioral sensitization with repeated cocaine administration than do nulliparous age-matched females. The experiments proposed here will test the hypothesis that beneficial effects of social bond formation during the maternal experience of caring for young (whether the female is parturient or not) can protect females from susceptibility for drug abuse. Specifically, experiments will examine if caring for young can affect cocaine self-administration behavior (i.e., the rate of acquisition, the motivation to self-administer cocaine, continuation of responding during periods of non-reinforcement, and persistence to take drug in the face of aversive outcomes), and/or the animals' endogenous response to repeated cocaine exposure using a behavioral sensitization paradigm and in vivo microdialysis. PUBLIC HEALTH RELEVANCE: The experiments proposed here will test the hypothesis that beneficial effects of social bond formation during the maternal experience of caring for young (whether the female is parturient or not) can protect females from susceptibility for drug abuse. Data generated from these experiments will provide a first step towards delineating neurobiological/neurobehavioral mechanisms that may attenuate drug taking in females and lead to identification of new methods to help treat women who are at risk for drug addiction.