Individual Differences in Mesolimbic Dopamine Systems

描述(申请人摘要)：有相当多的个人 在药物滥用的脆弱性方面的差异。我们正在探索这种可能性 这种差异可能反映了早期经验对发育的影响。 调节毒品寻觅行为的神经系统。虽然它的确切作用是 中脑皮质边缘多巴胺系统在药物自我给药中的作用尚不清楚， 这一系统似乎确实与药物自我管理密切相关。 我们发现，在生命早期母体分离会减少多巴胺转运体 水平和增加细胞外多巴胺对应激的反应。 大鼠体内的伏隔神经。同样，这些动物在压力诱导下表现出更强的 安非他明对运动效应的敏化和行为增强 对可卡因的反应性。在这里提出的研究中，我们正在研究 母体分离对多巴胺和兴奋性氨基酸的影响 前额叶皮质对压力的反应。正常情况下，增加的多巴胺 前额叶皮质的活动抑制了下丘脑多巴胺的释放。 伏伏草。这些研究还考察了偏侧性的问题，比较 前额叶皮质左右区域的反应。一秒钟内 我们正在研究个体差异之间的关系的一组研究 在下丘脑-垂体-肾上腺对应激的反应中以及在 中皮质边缘多巴胺系统。成年动物暴露于母体 早期生活中的分离表现出对压力的HPA反应增加， 与促肾上腺皮质激素释放因子(CRF)mRNA水平升高有关 下丘脑的室旁核和杏仁核的中央核。 Piazza和他的同事认为肾上腺糖皮质激素调节 伏隔核多巴胺对应激的反应以及行为 对反复的压力或精神刺激性药物的使用敏感。这些 研究考察了母体分离对 提升的多巴胺系统可能在一定程度上是由 糖皮质激素和/或CRF活性。最后，我们正在研究潜在的 选择性神经肽调节剂对皮质边缘多巴胺的影响 脑啡肽和强啡肽系统。这些研究是基于 麦克尤恩实验室的最新发现表明，这些神经肽系统可能 调节个体对压力的行为反应的差异。我们觉得 这些研究将为我们提供对早期 环境事件可能有助于个人的发展 调节寻药行为的神经系统的差异。

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.