High-throughput Identification of Non-hallucinogenic Psychoplastogens for Treating Addiction

项目总结/摘要 神经回路的病理变化是多种神经精神疾病的基础，包括成瘾和 萧条从人体成像、死后分析和动物模型中积累的证据表明， 前额叶皮层（PFC）神经元的萎缩-包括树突状动脉的收缩， 树突棘和突触密度的减少在物质使用的病理生理学中起着关键作用 疾病（SUD）。前额叶皮层是众所周知的调节边缘奖励电路，调节注意力，并发挥顶部- 因此，PFC中神经元的萎缩被认为会恶化 SUD通过减少执行控制，加剧冲动，并导致药物线索消失的缺陷， 回忆假设旨在恢复PFC结构/功能的治疗策略具有广泛的 SUD的治疗潜力。Psychoplastogens-激活TrkB信号传导并作为 脑源性神经营养因子（BDNF）模拟物-能够迅速恢复PFC的功能连接 并在单次给药后产生持久的治疗效果。然而，最突出的 精神致形体--包括多巴胺能致幻剂--都能产生幻觉，这极大地限制了他们的 治疗潜力最近有证据表明这些药物的致幻作用 可能不是其治疗特性所必需的，并且第一个非致幻性精神致活素是 我们的团队在过去的一年里。一种这样的分子，被称为tabernanthropy（TBG）， 在海洛因自我给药的啮齿动物模型中， 抗上瘾的迷幻药TBG的出现代表了治疗的一个令人兴奋的新方向 成瘾，但迫切需要开发新的检测方法，使快速识别TBG样 具有优化的功效和安全性特征的分子。我们的总体目标是开发高通量 鉴定非致幻性精神致活素的方法， 治疗效果为了实现这一目标，我们开发了一种基因编码的5-HT 2AR- 基于生物传感器，能够预测小的致幻性和精神可塑性 分子。拟议中的研究涉及使用这种技术来快速识别新的非致幻药物。 用于治疗成瘾以及探测与多巴胺，阿片样物质， 和大麻素受体。我们还建议进行研究来阐明分子和电路水平的机制 抗成瘾非致幻精神可塑剂TBG最终，这里描述的工作将填补差距 在我们关于如何最好地快速筛选非致幻性精神致质体的知识中， 合理设计更安全、非致幻的致幻剂替代品，用于治疗SUD和相关并发症， 病态疾病，如抑郁症。

PROJECT SUMMARY/ABSTRACT Pathological changes in neural circuitry underly a variety of neuropsychiatric diseases including addiction and depression. Accumulating evidence from human imaging, postmortem analysis, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC)—including the retraction of dendritic arbors, loss of dendritic spines, and reduction in synapse density—plays a key role in the pathophysiology of substance use disorders (SUDs). The PFC is well known to regulate limbic reward circuitry, modulate attention, and exert top- down control over drug-seeking behavior, and thus, the atrophy of neurons in the PFC is believed to worsen SUD by reducing executive control, exacerbating impulsivity, and leading to deficits in the extinction of drug-cue memories. Therapeutic strategies aimed at restoring PFC structure/function are hypothesized to have broad therapeutic potential for SUDs. Psychoplastogens—small molecules that activate TrkB signaling and serve as brain-derived neurotrophic factor (BDNF) mimetics—are able to rapidly restore functional connectivity in the PFC and produce long-lasting therapeutic effects after a single administration. However, the most prominent psychoplastogens—including serotonergic psychedelics—all produce hallucinations, which greatly limit their therapeutic potential. Recently, evidence has emerged suggesting that the hallucinogenic effects of these drugs may not be necessary for their therapeutic properties, and the first non-hallucinogenic psychoplastogens were introduced by our group this past year. One such molecule, known as tabernanthalog (TBG), produces both rapid and sustained anti-addictive effects in rodent models of heroin self-administration, much like the known anti-addictive psychedelic ibogaine. The advent of TBG represents an exciting new direction for the treatment of addiction, but there is an urgent need to develop new assays enabling the rapid identification of TBG-like molecules with optimized efficacy and safety profiles. Our overall objective is to develop high-throughput methods for identifying non-hallucinogenic psychoplastogens that, like TBG, can produce long-lasting therapeutic effects. To achieve this goal, we have developed psychLight—a genetically encoded, 5-HT2AR- based biosensor capable of predicting both the hallucinogenic and psychoplastogenic properties of small molecules. The proposed studies involve the use of this technology to rapidly identify new non-hallucinogenic psychoplastogens for treating addiction as well as probing potential 5-HT2AR interactions with dopamine, opioid, and cannabinoid receptors. We also propose studies to elucidate the molecular and circuit-level mechanisms of the anti-addictive, non-hallucinogenic psychoplastogen TBG. Ultimately, the work described here will fill the gap in our knowledge about how best to rapidly screen for non-hallucinogenic psychoplastogens, which will enable the rational design of safer, non-hallucinogenic alternatives to psychedelics for treating SUDs and related co- morbid diseases such as depression.