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，最近的一份报告称，12-17岁的可卡因吸毒者中有56%是女性。与男性相比，女性在吸毒上瘾的所有阶段升级得更快，这使得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，甚至增加药物使用。虽然有可能开发针对女性可卡因滥用的针对性别的药物治疗，但也需要非药物治疗。对实验室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强大的社会纽带具有潜在的保护作用。在老鼠身上形成的最强大的社会纽带是母婴纽带。在饲养后代后，雌性大鼠表现出学习和记忆的改善，探索和觅食能力的增强，认知功能随年龄的下降得到缓解，神经行为压力和恐惧反应减少，即使在后代断奶后也是如此。这些有益的变化已经被证明在后代离开巢后持续了几个月，这表明相对永久性的神经重组。重要的是，母亲行为的这些好处发生在未分娩的养母和被诱导采取母亲行为的男性身上，这表明怀孕和分娩不是看到这些好处的必要条件。滥用药物和社会纽带的形成都会导致中脑边缘多巴胺通路的神经元靶点发生变化，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，这种神经系统形成对替代目标的依恋的能力就会降低。因此，与雌性结成对的雄性草原田鼠不会对低剂量的苯丙胺产生条件性偏爱，而未结合的雄性则会。同样，表现出对苯丙胺敏感的雄性田鼠，当呈现给雌性田鼠时，不容易形成成对的纽带。我们实验室的初步数据显示，与未分娩的年龄匹配的女性相比，初产女性在重复注射可卡因后表现出较少的行为敏感化。这里提出的实验将检验这样一种假设，即在照顾孩子的母亲经历期间(无论女性是不是临产的)，社会纽带的形成有益于保护女性免受药物滥用的影响。具体地说，实验将检验照顾幼年是否会影响可卡因自我管理行为(即获得可卡因的速度、自我管理可卡因的动机、在非强化期间的持续反应以及在面对不良结果时坚持服药)，和/或使用行为敏化范式和体内微透析对反复接触可卡因的动物的内源性反应。 公共卫生相关性：这里提出的实验将检验这样一种假设，即在照顾幼崽的母亲经历期间(无论女性是不是分娩的)，社会纽带的形成有益于保护女性免受药物滥用的影响。这些实验产生的数据将为描绘可能减少女性吸毒的神经生物学/神经行为机制提供第一步，并导致确定帮助治疗有毒瘾风险的女性的新方法。

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.