Cocaine Alterations of Maternal Dopamine Transients

描述（由申请人提供）：人类和动物研究中有充分证据表明，药物滥用会扰乱孕产妇行为，导致孕产妇对婴儿的忽视程度更高，但相关的神经机制仍不清楚。一些啮齿动物研究表明，与未接触可卡因的母亲相比，接触可卡因的母亲可能不太愿意花时间与幼崽在一起。一种可能性是，幼犬的刺激，这是众所周知的，以促进母亲的反应，在正常的母亲，被认为是较少的动机可卡因暴露的母亲。动机性行为是由多巴胺在中脑神经元通路中的活动调节的。腹侧纹状体中的快速多巴胺释放事件，即多巴胺瞬变，是在检测到显著刺激时发生的奖励预测的神经信号，并且通常在接近目标之前。我们假设大鼠母亲的多巴胺瞬变是由幼鼠刺激触发的，并促进正常的幼鼠定向的母体行为，而可卡因治疗的母亲已经钝化了DA释放到幼鼠的刺激，这与母体反应较少相关，并由母体多巴胺改变可卡因和可卡因暴露幼鼠产生的刺激改变的组合驱动。我们建议使用快速扫描循环伏安法来测量多巴胺释放在一个既定的啮齿动物模型的母性行为。因此，我们将确定是否母亲可卡因暴露在怀孕期间，这减少了小狗的行为，也减少了母亲多巴胺释放到小狗的线索。我们将使用两步的方法：我们将在啮齿动物母亲中描述多巴胺瞬变，首先是因为它们对窝仔的反应，其次是对与整窝仔分开的选定幼仔线索的反应。总之，这些实验的结果将（1）确定特定的小狗相关刺激，正常的母亲行为和多巴胺瞬变之间的关系，（2）验证妊娠期可卡因使用如何改变母婴二元体中的这些关系。这些研究的数据将为未来的研究提供坚实的基础，这些研究涉及母体行为中阶段性多巴胺信号的因果关系和生化基础以及慢性可卡因对其的失调，并将告知我们对滥用药物母亲中人类母体忽视的理解。

DESCRIPTION (provided by applicant): Disruption of maternal behavior by substance abuse resulting in higher levels of maternal neglect towards infants is well documented in human and animal research, while the associated neural mechanisms remain unclear. Several rodent studies indicate that cocaine-exposed maternal females may be less motivated to spend time with pups compared to non-cocaine exposed mothers. One possibility is that pup stimuli, which are known to promote maternal responding in normal mothers, are perceived as less motivating in cocaine-exposed mothers. Motivated behaviors are modulated by dopamine activity in the mesoaccumbens pathway. Fast dopamine release events in the ventral striatum, i.e. dopamine transients, are neural signals of reward prediction occurring at the detection of salient stimuli and often precede approach to a reinforcer. We hypothesize that dopamine transients in rat mothers are triggered by pup stimuli and facilitate normal pup-directed maternal behaviors, while cocaine-treated mothers have blunted DA release to stimuli from their pups that correlates with less maternal response and is driven by a combination of maternal dopamine alterations to cocaine and altered stimuli produced by the cocaine-exposed pups. We propose to use fast scan cyclic voltammetry to measure dopamine release in an established rodent model of maternal behavior. Thus, we will determine whether maternal cocaine exposure during pregnancy, which reduces pup-directed behaviors, also diminishes maternal dopamine release to pup cues. We will use a two-step approach: we will profile dopamine transients in rodent mothers first as they respond to their litters, and second in response to selected pup cues separately from the whole litter. Together, results from these experiments will (1) determine relationships between specific pup-associated stimuli, normal maternal behavior and dopamine transients, and (2) verify how gestational cocaine use alters these relationships in the mother-infant dyad. The data from these studies will provide a solid foundation for future research concerning the causality and biochemical underpinnings of phasic dopamine signals in maternal behavior and their dysregulation by chronic cocaine and will inform our understanding of human maternal neglect in drug-abusing mothers.