Sensitive periods, development, and substance abuse

描述(由申请人提供)：药物使用通常在青春期中期开始，但如果发生在青春期较早/儿童后期，药物使用与重大的、终身成瘾的责任有关。识别高危人群对于早期干预/预防至关重要，并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的机制，并且证据应该是因果的，而不是像以前的研究那样相互关联。此外，这种理解需要扩展到不成熟的女性，那里对神经变化和药物敏感性知之甚少。在这里，我们建议建立在我们大量的初步数据的基础上，这些数据利用高度新颖和创新的方法来表明：a)相对于年轻和老年大鼠，青春期雄性大鼠在前额叶皮质(PlPFC)的谷氨酸能神经元上D1多巴胺受体的表达增加，并且与这个年龄段的大鼠对药物相关线索的敏感性增加有关；b)通过慢病毒载体(CamKII)在PLPFC中基因工程上调谷氨酸神经元上的D1受体，增加对可卡因相关线索的偏好；c)GABA神经元和谷氨酸神经元(Synapsin.D1)上的基因工程D1受体表达并不增强药物线索的敏感性；D)幼年大鼠的求新欲与对可卡因相关环境的偏好相关(r=0.87)；e)D1多巴胺受体可引起血流模式随年龄的变化，这很可能反映了D1R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，以实验证明谷氨酸神经元上的D1受体位置是风险机制(目标I)。这些动物还将表明，由于plPFC内谷氨酸神经元上的D1受体(Aim I)，原始的、强烈的药物线索关联更难消除和恢复得更强。AIM II将确定幼年动物的新奇行为是否可以作为一种行为指标来确定药物线索敏感性的增加，以及这与D1受体的关系。同时运行的AIM IV将使用CamKII D1病毒和新颖性寻找来确定药物磁共振是否可以通过独特的血流模式识别这种风险的生物标记物。目标三将确定在最初接触毒品时更有利的环境(例如，家庭笼子)是否可以减少在以后生活中其他更突出的环境中寻找毒品的情况。总之，这些研究将确定单个生物标记物如何预测药物使用的风险，并影响药物滥用的持久风险。

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.