Stress & Vulnerability to Drug Abuse: Neural Correlates

描述（由申请人提供）：个人在其 有滥用药物并上瘾的倾向。 有些人可能会寻求毒品作为寻求感觉或冒险行为的一个方面。 其他人可能是由于社会或心理压力而这样做。的目的 这项建议是调查这些个体的神经生物学基础， 滥用药物的脆弱性的差异。基本前提是， 遗传、发育和环境因素的结合，导致 脆弱性的差异是在大脑中表达的，需要 在这个层面上理解。相关基因表达的主要位点是 很可能是在调节情绪的大脑回路中， 对压力和环境的反应， 成瘾和情绪障碍。 为了研究药物个体差异的神经基础， 虐待，这项建议依赖于一个行为模型，区分大鼠， 是从那些没有感觉或新奇的人那里获得的。这些 寻求刺激的动物学会了服用药物，如安非他明， 虽然药物对他们同样有益，但速度更快。我们计划 描述大鼠的基因表达模式， 感觉寻求行为的表现型。我们计划把重点放在与压力有关的 基因，并确定可能存在的独特的神经元表型 与寻求刺激和吸毒行为有关。然后我们计划使用 一个心理社会压力的模型，社会失败，研究这种影响， 强调吸毒行为的获得率和相关的 在这些不同的人的情绪回路中的基因表达模式 动物这些研究应该开始给我们一个一瞥基因表达如何 不同的虐待倾向个体的大脑回路可能不同 药物，以及社会压力如何影响这些系统，进一步改变 并导致独特的行为反应。

DESCRIPTION (provided by applicant): Individuals vary significantly in their propensity to experiment with drugs of abuse and to become addicted to them. Some may seek drugs as an aspect of sensation seeking or risk taking behavior. Others may do so as a result of social or psychological stress. The purpose of this proposal is to investigate the neurobiological basis for these individual differences in vulnerability to abusing drugs. The basic premise is that the combination of genetic, developmental and environmental factors that lead to differences in vulnerability is expressed in the brain, and needs to be understood at that level. The primary site of expression of relevant genes is likely in the context of the emotional brain circuits that regulate responsiveness to stress and to the environment, and that become dysregulated in addiction and in mood disorders. In order to investigate the neuronal basis of individual differences in drug abuse, this proposal relies on a behavioral model that distinguishes rats that are sensation or novelty-seeking from those that are not. These sensation-seeking animals learn to administer drugs, such as amphetamine, much more rapidly although the drugs are equally rewarding to them. We plan to characterize the patterns of gene expression in rats that exhibit different phenotypes of sensation-seeking behavior. We plan to focus on stress related genes and determine the possible presence of unique neuronal phenotypes associated with sensation-seeking and drug-taking behavior. We then plan to use a model of psychosocial stress, social defeat, to study the impact of such stress on the rate of acquisition of drug taking behavior and the associated patterns of gene expression in the emotional circuits of these differing animals. These studies should begin to give us a glimpse of how gene expression and brain circuits may differ in individuals with differing tendencies to abuse drugs, and how social stress can impact on these systems, further modifying them and leading to distinctive behavioral responses.