Cocaine disruption of maternal motivation: preference for pups vs. cocaine

描述（由申请人提供）：妇女在产后期间滥用可卡因与产妇护理功能失调有关，这可能对孩子产生严重的终身后果。在接下来的实验中使用的临床前模型采用了基于条件位置偏好程序的双重选择范式，为产后母鼠提供了与幼崽相关的环境和可卡因之间的选择。在一些雌性体内，可卡因的强化作用足以与母性动机竞争幼崽，而在另一些雌性体内，母性动机是更强大、更有弹性的力量。我们发现，当产后大鼠对可卡因或幼崽相关环境表现出动机性偏好时，包括内侧前额叶皮层（mPFC）、伏隔核（NA）和内侧视前区/腹侧床终纹核（mPOA/vBST）在内的离散脑区神经元被不同地激活。拟议的研究项目是一个正在进行的研究项目的一部分，该研究项目由NARSAD青年研究者奖资助，旨在测试一个假设，即对幼崽的偏好与可卡因相关的环境是由上述区域区域分布的神经元网络的协同活动调节的。我们将通过暂时灭活（布比卡因输注）这些位点，然后测试刺激相关的环境偏好，来确定这些位点在动机选择表达中的功能作用（Specific Aim I）。对早期直接基因产物cfo的免疫细胞化学分析将揭示神经元失活的区域特异性，以及随后在动机回路剩余关键成分中神经元活动的变化（Specific Aim II）。此外，关键区域内多巴胺（DA）和谷氨酸（GLU）神经传递对选择行为的因果贡献将通过特定部位输注选择性DA和GLU激动剂和/或拮抗剂来确定（specific Aim III）。这些实验将揭示哪些区域与小狗和可卡因寻求行为的动机选择反应有因果关系，并进一步揭示这些中枢神经系统位点如何相互作用以促进对一种刺激的选择。

DESCRIPTION (provided by applicant): Cocaine abuse in women during the postpartum period is associated with dysfunctional maternal care, which can have severe lifelong consequences for the child. The preclinical model used in the following experiments employs a dual-choice paradigm based on the conditioned place preference procedure to offer postpartum maternal rats a choice between environments associated with pups and cocaine. In some females, cocaine is reinforcing enough to compete with maternal motivation for pups, whereas in others maternal motivation is the stronger, more resilient force. We identified neurons within discrete brain regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NA) and medial preoptic area/ventral bed nucleus of the stria terminalis (mPOA/vBST) that are differentially activated when postpartum rats express a motivated preference for cocaine- or pup-associated environments. The proposed research project is part of an ongoing research project funded by a NARSAD Young Investigator Award, designed to test the hypothesis that preference for pups versus cocaine-associated environments is regulated by the concerted activity of regionally distributed networks of neurons in the regions mentioned above. We will determine the functional role of these sites in the expression of motivated choices by transiently inactivating (bupivacaine infusion) each of them and then testing stimulus-associated environment preference (Specific Aim I). Immunocytochemical analysis of the early immediate gene product cFos will reveal regional specificity of neuronal inactivation, and consequent changes in neuronal activity within the remaining key components of the motivational circuitry (Specific Aim II). Further, the causal contribution of dopamine (DA) and glutamate (GLU) neurotransmission within key regions to the choice behavior will be determined with site- specific infusion of selective DA and GLU agonists and/or antagonists (Specific Aim III). These experiments will uncover which regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how these CNS sites interact to promote the choice for one stimulus over the other. PUBLIC HEALTH RELEVANCE: The 2007 National Survey on Drug Use and Health (NSDUH) estimated the rate of cocaine use among pregnant women at 5.2%. Cocaine abuse in women during pregnancy and the postpartum period severely disrupts mother-infant interactions, which can have negative lifelong consequences for both members of the dyad, often including severe mental health consequences. Substance abuse remains a pressing public health problem that affects millions of women and their babies, and imposes enormous financial and social burdens on society. This application is focused in the understanding of the neural substrate that mediates the motivational aspects of maternal behavior during the postpartum period, particularly within the context of the disruptive effects of drugs with high abuse potential such as cocaine. Through a combination of neurobiological and behavioral techniques, this project will uncover which brain regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how they interact to promote the preference for one stimulus over the other. Stimulant abuse is an insidious and dangerous chronic recurring and relapsing disease. While the human condition is vastly more complex than our preclinical model, our data offer critical information of the fundamental neurobiological underpinning of the disruptive effect of cocaine on maternal motivation. This preclinical information might contribute to the development of strategies for treatments or methods of prevention of this tragic human condition, with particular emphasis in maintaining or restoring mother- infant bonding.