Individual Differences in Mesolimbic Dopamine Systems

中脑边缘多巴胺系统的个体差异

基本信息

批准号：
6327391
负责人：
Michael Joseph Meaney
金额：
$ 20万
依托单位：
MCGILL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-05 至 2004-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (applicant's abstract): There are considerable individual differences in vulnerability for drug abuse. We are exploring the possibility that variation might reflect the effects of early experience on the development of neural systems that mediate drug-seeking behavior. While the precise role of the mesocorticolimbic dopamine system in drug self-administration is not clear, this system does appear to be critically involved in drug self-administration. We found that maternal separation in early life decreases dopamine transporter levels and increases extracellular dopamine responses to stress in the n. accumbens in the rat. Likewise, these animals show increased stress-induced sensitization to the locomotor effects of amphetamine and increased behavioral responsivity to cocaine. In the studies proposed here we are examining the effects of maternal separation on dopamine as well as excitatory amino acid responses to stress in the prefrontal cortex. Normally, increased dopamine activity in the prefrontal cortex serves to inhibit dopamine release in the n. accumbens. These studies also examine the question of laterality, comparing responses in the left and right regions of the prefrontal cortex. In a second set of studies we are examining the relationship between individual differences in hypothalamic-pituitary-adrenal responses to stress and those observed in the mesocorticolimbic dopamine systems. Adult animals exposed to maternal separation in early life show increased HPA responses to stress that are associated with elevated levels of corticotropin-releasing factor (CRF) mRNA in the paraventricular n. of the hypothalamus and the central n. of the amygdala. Piazza and colleagues have suggested that adrenal glucocorticoids regulate dopamine responses to stress in the n. accumbens as well as behavioral sensitization to repeated stress or psychostimulant drug administration. These studies examine the possibility that the effects of maternal separation on ascending dopamine systems may be mediated, in part, by differences in glucocorticoid and/or CRF activity. Finally, we are examining the potential influence of selected neuropeptide regulators of mesocorticolimbic dopamine systems, such as enkephalin and dynorphin systems. These studies are based on recent findings from the McEwen lab that these neuropeptide systems might mediate individual differences in behavioral responses to stress. We feel that these studies will provide us with an understanding of the way in which early environmental events might contribute to the development of individual differences in neural systems that mediate drug-seeking behavior.

描述（申请人的摘要）：有很多个体药物滥用脆弱性的差异。我们正在探索可能性这种差异可能反映了早期经验对发展的影响介导寻求药物行为的神经系统。而精确的角色在药物自我给药中的中皮质糖多巴胺系统尚不清楚，该系统似乎确实与药物自我管理有关。我们发现早期的产妇分离会降低多巴胺转运蛋白水平并增加了细胞外多巴胺对n中压力的反应。大鼠的伏伏。同样，这些动物表现出增加的压力引起的对苯丙胺的运动作用和行为增加的敏感性对可卡因的反应。在这里提出的研究中，我们正在研究产妇分离对多巴胺以及兴奋性氨基酸的影响对额叶皮层的压力的反应。通常，多巴胺增加前额叶皮质中的活性可抑制n中的多巴胺释放。伏伏尔。这些研究还检查了横向性问题，比较前额叶皮层的左右区域的反应。一秒钟一组研究我们正在研究个体差异之间的关系在下丘脑 - 垂体 - 肾上腺对压力的反应中，中皮质糖多巴胺系统。成年动物暴露于母亲早期分离表明，HPA对压力的反应增加了与促脂蛋白释放因子（CRF）mRNA的水平升高有关室室n。下丘脑和中央n。杏仁核。广场及其同事表明肾上腺糖皮质激素调节多巴胺对n的压力反应。伏尊和行为对重复压力或精神刺激药物给药的敏感。这些研究检查了产妇分离对的可能性上升的多巴胺系统可能部分通过差异来介导糖皮质激素和/或CRF活性。最后，我们正在研究潜力中皮质糖多巴胺的选定神经肽调节剂的影响系统，例如Enkephalin和Dynorphin Systems。这些研究基于 McEwen实验室的最新发现，这些神经肽系统可能介导对压力的行为反应中的个体差异。我们感到这些研究将使我们了解早期的方式环境事件可能有助于个人的发展介导毒品行为的神经系统的差异。