Periadolescent Noradrenergic Regulation in the BNST

BNST 的青春期去甲肾上腺素能调节

• 批准号: 7104822
• 负责人: DANNY G WINDER
• 金额: $ 29.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104822
• 关键词: AMPA receptors; NMDA receptors; adrenergic receptor; age difference; anxiety; behavioral /social science research tag; brain regulatory center; central nervous system stimulants; drug abuse; electrodes; electrophysiology; glutamates; juvenile animal; laboratory mouse; long term potentiation; mature animal; neural transmission; neurotransmitter transport; norepinephrine; psychological stressor; radioimmunoassay; receptor expression; thalamus; voltage /patch clamp

DESCRIPTION (provided by applicant): Epidemiological evidence suggests that there is an inverse correlation between the age of first exposure to a drug of abuse and the likelihood of developing dependence, suggesting that periadolescence is a time of high vulnerability to drugs of abuse compared with adulthood. One key difference between periadolescents and adults is in their respective responses to stressors. Periadolescence is associated with a period of increased risk-taking, which is accompanied by hyporesponsiveness to many stressors compared to adults. In contrast, periadolescent animals have higher basal levels of circulating corticosterones, and under certain contexts appear more anxious than adults. Stress and anxiety play critical roles in drug abuse, thus an understanding of the basic mechanisms underlying these age-specific differences in anxiety-related behaviors will lead to more specific and age-appropriate therapeutic interventions both for drug abuse and anxiety disorders in general. The ventral noradrenergic bundle (VNAB) emanating from the nucleus of the solitary tract plays a key role in stress/anxiety responses. Lesions of the VNAB or manipulations of noradrenergic transmission within the major target of this projection, the bed nucleus of the stria terminalis (BNST), abolish stress-induced reinstatement of cocaine intake and conditioned place aversion to morphine withdrawal. The BNST is an assembly of sub-nuclei within the extended amygdala with rich interconnections between stress and reward centers. Stimulation of the anterolateral regions of the BNST evokes firing of dopaminergic neurons of the VTA, as well as increases PVN output, increasing peripheral corticosterone levels. Thus altering the level of output of the BNST would be predicted to have a dramatic impact on behavioral responses to drugs of abuse. We have identified two adrenergic receptors that play opposing roles in regulating inputs to the BNST. Here we will test the hypothesis that this regulation is altered in the periadolescent compared to the adult BNST. We will also determine whether psychostimulants, which indirectly target these receptors through altering endogenous catecholamine levels, produce similar effects on transmission. Finally, we will assess the impact of alterations in the relative levels of the receptors on both regulation of transmission and basal anxiety levels by screening recombinant inbred strains of mice (BxDs) with varying levels of receptor expression.

描述（由申请人提供）：流行病学证据表明，首次接触滥用药物的年龄与产生依赖性的可能性之间存在负相关，这表明与成年期相比，青春期是更容易滥用药物的时期。 青春期和成人之间的一个关键区别在于他们各自对压力源的反应。 青春期与冒险行为增加的时期相关，与成年人相比，伴随着对许多压力源的反应低下。 相比之下，青春期动物的循环皮质酮基础水平较高，并且在某些情况下显得比成年人更焦虑。 压力和焦虑在药物滥用中发挥着关键作用，因此，了解焦虑相关行为中这些年龄特异性差异的基本机制将有助于针对药物滥用和一般焦虑症采取更具体和适合年龄的治疗干预措施。 从孤束核发出的腹侧去甲肾上腺素束（VNAB）在应激/焦虑反应中起着关键作用。 VNAB 的损伤或该投射的主要目标（即终纹床核 (BNST)）内去甲肾上腺素能传输的操纵，消除了压力诱导的可卡因摄入恢复和对吗啡戒断的条件性厌恶。 BNST 是扩展杏仁核内亚核的集合，在压力中心和奖励中心之间具有丰富的互连。 刺激 BNST 前外侧区域会引起 VTA 多巴胺能神经元的放电，并增加 PVN 输出，从而增加外周皮质酮水平。 因此，改变 BNST 的输出水平预计会对滥用药物的行为反应产生巨大影响。 我们已经确定了两种肾上腺素能受体，它们在调节 BNST 的输入中发挥相反的作用。 在这里，我们将检验这样的假设：与成人 BNST 相比，这种调节在青春期期间发生了改变。 我们还将确定通过改变内源性儿茶酚胺水平间接靶向这些受体的精神兴奋剂是否对传播产生类似的影响。 最后，我们将通过筛选具有不同受体表达水平的重组近交系小鼠（BxD）来评估受体相对水平的变化对传播调节和基础焦虑水平的影响。