Cocaine Alterations of Maternal Dopamine Transients

描述(由申请人提供)：在人类和动物研究中，药物滥用导致母亲对婴儿的忽视程度更高，从而扰乱了母亲的行为，而相关的神经机制仍不清楚。几项啮齿动物研究表明，与未接触可卡因的母亲相比，接触可卡因的雌性母鼠可能没有那么有动力与幼崽共度时光。一种可能性是，幼崽刺激被认为在正常母亲中促进母体反应，但在接触可卡因的母亲中被认为激励较少。动机行为受中隔伏隔通路中多巴胺活性的调节。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赏预测的神经信号，通常发生在接近增强器之前。我们假设，大鼠母亲体内的多巴胺瞬变是由幼鼠刺激触发的，并促进了正常的幼鼠引导的母体行为，而可卡因治疗的母亲减弱了对幼鼠刺激的DA释放，这与较少的母体反应相关，并且是由母体对可卡因的多巴胺改变和暴露于可卡因的幼鼠产生的改变刺激的组合驱动的。我们建议使用快速扫描循环伏安法来测量已建立的母性行为啮齿动物模型中的多巴胺释放。因此，我们将确定怀孕期间母体接触可卡因是否也会减少母体对幼体线索的多巴胺释放。我们将使用两步法：我们将首先分析啮齿动物母亲对它们的幼崽做出反应时的多巴胺瞬变，然后分别对选定的幼崽与整个幼崽做出反应。总之，这些实验的结果将(1)确定特定幼崽相关刺激、正常母体行为和多巴胺瞬变之间的关系，以及(2)验证妊娠期可卡因的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关于母体行为中的相性多巴胺信号的因果关系和生化基础以及慢性可卡因对它们的失调的研究提供坚实的基础，并将有助于我们对吸毒母亲的人类母性忽视的理解。

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.