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 由于甲基苯丙胺（meth）使用障碍的普遍存在，给治疗带来了独特的挑战。 诱发的神经认知缺陷这些缺陷会导致持续的复发脆弱性并使情况复杂化。 在这里，我们利用啮齿动物模型来扩展自我管理（SA）冰毒的使用。 捕获了在冰毒使用者中观察到的许多症状，例如冰毒摄入量的增加、更高的倾向 复发、认知不灵活和情景记忆缺陷因此，该模型非常适合。 研究持久性甲基苯丙胺引起的缺陷的神经生物学并筛选潜在的新药物 使用该模型，我们报道了 SA meth 细胞表面（但不是全部）表达。 前额皮质 (PFC) 中的代谢型谷氨酸受体 (mGlu) 2/3 可持续长达 30 天 这一发现与冰毒使用障碍高度相关，因为： a) PFC 中 mGlu2/3 的正常功能是 认知最佳表现所必需的，b）增加神经活动并增强谷氨酸释放 在寻求甲基苯丙胺过程中观察到的 PFC 可能是由于 mGlu2/3 对谷氨酸能的控制减弱 神经传递，c) mGlu2/3 的全身和 PFC 内激活持续减少药物寻求。 然而，这些研究并没有从分子或药理学角度将 mGlu2 与 3 区分开来，并且具有重要意义。 当单独针对每种受体时，信号传导和行为输出会发生差异。 现有的药理学工具可以逆转 mGlu2（或 3）受体功能的丧失。 意义重大，因为它将是第一个在 meth 之后单独评估 mGlu2 与 3 的表面表达 SA，或其他，这也将是第一个将性别差异视为此类表达的因素。 创新源于开发新工具（干扰肽）以增加 mGlu2(3) 表面 最后，我们的目标是开发一种高度转化的鼻内注射剂。 我们已经发现这种肽的施用途径将允许选择性恢复。 我们将测试有慢性冰毒暴露史的受试者的 mGlu2 和/或 3 表面表达和功能。 该假设有以下具体目标： 目标 1 - 评估表面可用性和功能的性别差异 mGlu2 和 mGlu3 在 PFC 中的含量，目标 2 - 开发和优化干扰肽的体内递送 逆转 PFC 中 mGlu2（或 3）表面表达和功能的后甲基变化来实现这些。 为了实现雄心勃勃的目标，我们建议开发创新工具——受体特异性干扰肽——证据。 基于的预测是，这些肽将使 mGlu2(3) 的表面表达/功能正常化，而无需 总之，所提出的实验将产生传统受体配体的潜在副作用。 评估皮质 mGlu2(3) 受体作为开发新型神经生物学靶标的效用 治疗，可用于改善认知能力并降低冰毒复发的可能性。