Developing novel tools for targeting mGlu2(3) receptors in methamphetamine addiction.

开发针对甲基苯丙胺成瘾中的 mGlu2(3) 受体的新工具。

• 批准号: 9806929
• 负责人: Marek Schwendt
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806929
• 关键词: Abstinence; Agonist; Agreement; Animals; Behavioral; Binding; C-terminal; Cell physiology; Cell surface; Cells; Chronic; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Episodic memory; Female; Foundations; Glutamates; Goals; Human; Hyperactive behavior; Intake; Intranasal Administration; Investigation; Knowledge; Ligands; Location; Masks; Mediating; Memory impairment; Mental Health; Metabotropic Glutamate Receptors; Methamphetamine; Methamphetamine dependence; Modeling; Neurobiology; Neurocognitive Deficit; Neurons; Output; Penetration; Peptides; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Prevalence; Protein Kinase C; Public Health; Publishing; Rattus; Receptor Cell; Recording of previous events; Recovery; Relapse; Reporting; Reversal Learning; Rodent Model; Role; Route; Self Administration; Sex Differences; Short-Term Memory; Signal Transduction; Surface; Symptoms; Testing; Time; Work; base; cell type; clinically relevant; cognitive performance; comparative efficacy; craving; episodic like memory; evidence base; experience; experimental study; follow-up; high risk; improved; in vivo; innovation; methamphetamine effect; methamphetamine exposure; methamphetamine use; methamphetamine user; neuroadaptation; neurotransmission; novel; novel therapeutics; positive allosteric modulator; prevent; receptor; receptor function; relapse risk; restoration; screening; side effect; stem; success; tool

ABSTRACT Methamphetamine (meth) use disorder poses unique challenges for treatment due to the prevalence of meth- induced neurocognitive deficits. These deficits contribute to persistent relapse vulnerability and complicate recovery for meth users. Here we utilize a rodent model of extended access to self-administered (SA) meth that captures many symptoms observed in meth users, such as escalation of meth intake, higher propensity to relapse, cognitive inflexibility and deficits in episodic-like memory. Thus, this model is highly suitable for investigation of neurobiology underlying persistent meth-induced deficits and for the screening of potential novel therapeutics. Using this model, we have reported that SA meth reduces cell surface (but not total) expression of metabotropic glutamate receptors (mGlu) 2/3 in the prefrontal cortex (PFC) that persist for up to 30 days of abstinence. This finding is highly relevant for meth use disorder as: a) normal function of mGlu2/3 in the PFC is necessary for optimal cognitive performance, b) increased neuronal activity and enhanced glutamate release in the PFC observed during meth-seeking could be attributed to reduced control of mGlu2/3 over glutamatergic neurotransmission, and c) systemic and intra-PFC activation of mGlu2/3 consistently reduces drug-seeking. However, these studies did not molecularly or pharmacologically separate mGlu2 from 3, and significant differences in signaling and behavioral output occur when each receptor alone is targeted. Furthermore, no pharmacological tools exists that would reverse the loss of mGlu2 (or 3) receptor function. The present proposal is significant because it will be the first to evaluate the surface expression of mGlu2 vs. 3 separately after meth SA, or otherwise. It will also be the first to consider sex-differences as a factor in such expression. This proposal’s innovation stems from the development of novel tools (interference peptides) to increase mGlu2(3) surface availability/function after their in vivo administration. Finally, we aim to develop a highly-translational intranasal route of administration of such peptides. We hypothesize that this approach will allow for selective restoration of mGlu2 and/or 3 surface expression and function in subjects with a history of chronic meth exposure. We will test this hypothesis in the following specific aims: Aim 1- Evaluate sex-differences in surface availability and function of mGlu2 and mGlu3 in the PFC, and Aim 2- Develop and optimize the in vivo delivery of interference peptides that reverse post-meth changes in mGlu2 (or 3) surface expression and function in the PFC. To achieve these ambitious aims, we propose to develop innovative tools – receptor-specific interference peptides. Evidence- based prediction is that these peptides will normalize the surface expression/function of mGlu2(3) without the potential side-effects produced by traditional receptor ligands. In summary, the proposed experiments will evaluate the utility of cortical mGlu2(3) receptors as a target for development of novel, neurobiologically-based treatments, that can be used to improve cognitive performance and reduce the vulnerability to meth relapse.

抽象的 甲基苯丙胺（甲基苯丙胺（Methamine 诱发神经认知缺陷。这些缺陷导致持续的退休脆弱性并变得复杂 冰毒用户的恢复。在这里，我们利用了一种扩展访问自我管理（SA）甲基甲基苯丙胺的啮齿动物模型 捕获甲基苯丙胺使用者中观察到的许多症状 复发，认知的僵化性并在类似情节的记忆中定义。那是该模型非常适合 研究神经生物学潜在的持久性甲基甲基诱导的缺陷，并筛查潜在的新型 治疗。使用此模型，我们报告了SA仪表降低了细胞表面（但不是总的）表达 前额叶皮层（PFC）中2/3的代谢型谷氨酸受体（MGLU），最多持续30天 节制。该发现与甲基甲基甲基苯丙胺障碍高度相关：a）PFC中MGLU2/3的正常功能为 最佳认知性能所需的必要 在寻求甲基甲基甲基苯丙胺过程中观察到的PFC归因于谷氨酸能对MGLU2/3的控制减少 神经传递，以及c）MGLU2/3的全身性和PFC激活始终减少寻求药物。 但是，这些研究并未将MGLU2与3个分子或药物分离，并且显着 单独针对每个受体时，信号传导和行为输出的差异就会发生。此外，不 存在药理学工具可以扭转MGLU2（或3）受体功能的丧失。目前的提议 之所以意义 SA或其他。这也将是第一个将性差异视为这种表达的因素的人。该提议的 创新步骤从开发新工具（干扰肽）到增加MGLU2（3）表面 其体内给药后的可用性/功能。最后，我们旨在发展高度翻译的鼻内 这种肽的给药途径。我们假设这种方法将允许选择性恢复 MGLU2和/或3表达表达和功能在具有慢性甲基暴露史的受试者中。我们将测试 以下特定目的的假设：目标1-评估表面可用性和功能中的性别差异 PFC中的mglu2和mglu3的of AIM 2-开发和优化干扰肽的体内递送 这种反向METH后MGLU2（或3）的表面表达和功能变化。实现这些 雄心勃勃的目标，我们建议开发创新的工具 - 特定于接收器的干扰肽。证据- 基于基于的预测是，这些肽将在没有MGLU2（3）的表面表达/功能中标准化 传统接收器配体产生的潜在副作用。总而言之，拟议的实验将 评估皮质MGLU2（3）受体的效用，作为新型，基于神经生物学的开发目标 治疗方法可用于改善认知能力并减少满足救济的脆弱性。