Individual Differences in Mesolimbic Dopamine Systems

描述（申请人摘要）：有相当多的个人 吸毒脆弱性的差异。我们正在研究 这种变化可能反映了早期经验对发展的影响， 调节寻药行为的神经系统。虽然确切的作用 药物自我给药中的中皮质边缘多巴胺系统尚不清楚， 该系统似乎与药物自我给药密切相关。 我们发现，母亲在生命早期的分离减少多巴胺转运蛋白， 水平和增加细胞外多巴胺反应的压力在n. 老鼠体内的粘液同样，这些动物表现出增加的压力诱导的 对安非他明的运动效应敏感， 对可卡因的反应在这里提出的研究中，我们正在研究 母亲分离对多巴胺和兴奋性氨基酸的影响 对压力的反应。正常情况下，多巴胺增加 前额叶皮层的活动用于抑制N中的多巴胺释放。 快来这些研究还探讨了偏侧性问题，比较了 前额叶皮层左右两侧的反应。在第二 我们正在研究个体差异之间的关系 在下丘脑-垂体-肾上腺对应激的反应中， 中皮质边缘多巴胺系统暴露于母体的成年动物 在早期生活中的分离表明HPA对压力的反应增加， 与促肾上腺皮质激素释放因子（CRF）mRNA水平升高相关， 室旁神经下丘脑和中央神经节的神经元杏仁核的结构 Piazza及其同事认为肾上腺糖皮质激素调节 多巴胺对压力的反应。行为和行为 对反复压力或精神兴奋剂药物的敏感性。这些 研究调查了母亲分离对儿童的影响 多巴胺系统的上升可能部分是由 糖皮质激素和/或CRF活性。最后，我们正在研究 中皮质边缘多巴胺神经肽调节剂的选择性影响 系统，如脑啡肽和强啡肽系统。这些研究是基于 麦克尤恩实验室最近的发现表明，这些神经肽系统可能 调解压力行为反应的个体差异。我们觉得 这些研究将使我们了解早期 环境事件可能有助于个人的发展 神经系统的差异，介导药物寻求行为。

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.