Sensitive periods, development, and substance abuse

敏感期、发育和药物滥用

• 批准号: 8207888
• 负责人: SUSAN L ANDERSEN
• 金额: $ 35.55万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207888
• 关键词: Address; Adolescence; Adolescent; Adult; Age; Agonist; Alcohol or Other Drugs use; Animals; Attention deficit hyperactivity disorder; Behavior; Behavioral; Benign; Biological Markers; Blood flow; Childhood; Clinical; Cocaine; Conduct Disorder; Confocal Microscopy; Cues; Data; Detection; Development; Diagnosis; Dopamine; Dopamine D1 Receptor; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Early Diagnosis; Early treatment; Engineered Gene; Engineering; Environment; Exposure to; Extinction (Psychology); Female; Functional Magnetic Resonance Imaging; Genetic Engineering; Glutamates; Goals; Home environment; Immunohistochemistry; Individual; Lead; Lentivirus Vector; Life; Location; Magnetic Resonance Imaging; Maintenance; Male Adolescents; Maps; Mediating; Metric; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Odors; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Population; Prefrontal Cortex; Prevention; Procedures; Property; Rattus; Relative (related person); Research; Risk; Role; Running; Saline; Scanning; Screening procedure; Staging; Substance abuse problem; Synapsins; Time; Viral; Viral Vector; Virus; Vulnerable Populations; Work; addiction; age related; base; cocaine exposure; conditioning; drug of abuse; drug sensitivity; gamma-Aminobutyric Acid; innovation; instrument; juvenile animal; male; novel; preclinical study; preference; prophylactic; public health relevance; receptor; receptor density; receptor expression; relating to nervous system; response

DESCRIPTION (provided by applicant): Substance use typically begins in mid-adolescence, but when it occurs earlier in adolescence/late childhood, drug use is associated with significant, life-long addiction liability. Identification of at-risk individuals is vital for early intervention/prevention and may have the greatest impact on reducing addiction long-term. However, this approach requires an understanding of the mechanism of risk and the proof should be causal, and not correlational, as in previous studies. In addition, this understanding needs to be extended to immature females, where extreme little is know about neural changes and drug sensitivity. Here, we propose to build on our substantial preliminary data that utilizes highly novel and innovative approaches to show the following: a) elevated D1 dopamine receptor expression on glutamatergic neurons in the prelimbic prefrontal cortex (plPFC) is observed in adolescent male rats relative to younger and older rats, and is associated with increased sensitivity to drug-associated cues at this age; b) gene engineered elevations in D1 receptors on glutamate neurons with a lentiviral vector (CamKII.D1) in the plPFC increases preferences to cocaine-associated cues; c) gene engineered D1 receptor expression on both GABA and glutamate neurons (Synapsin.D1) does not enhance drug-cue sensitivity; d) novelty-seeking in juvenile rats correlates with preferences for cocaine-associated environments (r=0.87); e) D1 dopamine receptors produce age-dependent changes in blood flow patterns that most likely reflect the distribution of D1 receptors on glutamate and GABA neurons. In a set of studies that are highly consistent with # PA-07-226, we propose to use these two viral vectors to increase (a) or decrease (b) sensitivity to drug-related cues to experimentally show that D1 receptor location on glutamate neurons is the risk mechanism (Aim I). These same animals will also show that the original, strong drug-cue associations are more difficult to extinguish and reinstate more strongly as a result of D1 receptors on glutamate neurons within the plPFC (Aim I). Aim II will determine whether novelty-seeking in juvenile animals can serve as an behavioral metric to identify increased drug-cue sensitivity and how this relates to D1 receptors. Aim IV, which runs concurrently, will use the CamKII.D1 virus and novelty-seeking to determine whether pharmacoMRI can identify this biomarker of risk through unique blood flow patterns. Aim III will determine whether a more benign environment at the time of initial drug exposure (e.g., home- cage) can reduce drug-seeking in other more salient environments later in life. Together, these studies will determine how a single biomarker predicts risk for substance use and influence enduring risk of drug abuse. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine whether elevated expression of the D1 dopamine receptor in the prefrontal cortex contributes to vulnerability to substance use in developing animals and can serve as a biomarker for early detection. D1 dopamine receptors are transiently over-expressed on specific neurons (e.g., glutamate) during adolescence, which is hypothesized to underlie enhanced vulnerability to cocaine at this stage. Here, we will use gene engineering to manipulate D1 receptor expression to conclusively show that this receptor underlies increased sensitivity to the initial formation of cocaine-associations and their maintenance, which may be detected by behavioral screening early and/or detected with pharmacoMRI and associated blood flow changes.

描述（由申请人提供）：药物使用通常开始于青春期中期，但当它发生在青春期早期/儿童晚期时，药物使用与显着的、终生的成瘾倾向相关。识别高危人群对于早期干预/预防至关重要，并且可能对长期减少成瘾产生最大影响。然而，这种方法需要了解风险机制，并且证据应该是因果关系，而不是像以前的研究那样是相关的。此外，这种理解需要扩展到不成熟的女性，因为她们对神经变化和药物敏感性知之甚少。在这里，我们建议在大量初步数据的基础上，利用高度新颖和创新的方法来展示以下内容：a）相对于年轻大鼠，在青春期雄性大鼠中观察到前边缘前额皮质（plPFC）谷氨酸能神经元上的 D1 多巴胺受体表达升高和老年大鼠，并且与该年龄段对药物相关线索的敏感性增加有关； b) 利用plPFC中的慢病毒载体（CamKII.D1）对谷氨酸神经元上的D1受体进行基因工程改造，增加了对可卡因相关线索的偏好； c) GABA 和谷氨酸神经元 (Synapsin.D1) 上的基因工程 D1 受体表达不会增强药物提示敏感性； d) 幼年大鼠的新奇寻求与对可卡因相关环境的偏好相关（r=0.87）； e) D1 多巴胺受体产生年龄依赖性的血流模式变化，这很可能反映了 D1 受体在谷氨酸和 GABA 神经元上的分布。在一组与 # PA-07-226 高度一致的研究中，我们建议使用这两种病毒载体来增加 (a) 或降低 (b) 对药物相关线索的敏感性，以通过实验证明 D1 受体位于谷氨酸上神经元是风险机制（目标 I）。这些相同的动物还将表明，由于 plPFC 内谷氨酸神经元上的 D1 受体，原始的、强烈的药物提示关联更难以消除和更强烈地恢复（目标 I）。目标 II 将确定幼年动物的新奇寻求是否可以作为行为指标来识别药物提示敏感性的增加以及这与 D1 受体的关系。同时运行的 Aim IV 将使用 CamKII.D1 病毒和新颖性来确定pharmacoMRI 是否可以通过独特的血流模式识别这种风险生物标志物。目标 III 将确定初次接触药物时的更良性环境（例如，家庭笼子）是否可以减少以后在其他更显着的环境中寻求药物。这些研究将共同​​确定单一生物标志物如何预测药物滥用风险并影响药物滥用的持久风险。 公共健康相关性：拟议研究的目标是确定前额皮质中 D1 多巴胺受体表达的升高是否会导致发育中动物对药物使用的脆弱性，并可作为早期检测的生物标志物。 D1 多巴胺受体在青春期期间在特定神经元（例如谷氨酸）上短暂过度表达，这被认为是这一阶段对可卡因的脆弱性增强的基础。在这里，我们将使用基因工程来操纵 D1 受体表达，以最终证明该受体是对可卡因关联的初始形成及其维持的敏感性增加的基础，这可以通过早期行为筛查和/或通过药物 MRI 和相关血液检测到流量变化。