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

摘要 由于冰毒的流行，甲基苯丙胺(冰毒)使用障碍对治疗构成了独特的挑战。 诱发的神经认知缺陷。这些缺陷导致持续的复发脆弱性，并使 冰毒使用者的康复。在这里，我们利用了一个啮齿类动物模型，该模型扩展了对自我管理(SA)冰毒的访问 捕获了在冰毒使用者中观察到的许多症状，如冰毒摄入量上升，更高的倾向 反复发作、认知僵化和情景样记忆缺陷。因此，该模型非常适合于 持续性冰毒致缺陷的神经生物学研究及潜在新基因的筛选 治疗学。利用这个模型，我们已经报道了SA METH降低了细胞表面(但不是全部)的表达 前额叶皮质(PFC)中2/3的代谢性谷氨酸受体(MGlu)持续长达30天 禁欲。这一发现与冰毒使用障碍高度相关，因为：a)mGlu2/3在PFC中的正常功能是 对最佳认知能力是必要的，b)增加神经元活动和增强谷氨酸释放 在寻找冰毒过程中观察到的PFC可能归因于mGlu2/3对谷氨酸能的控制减少 C)全身和PFC内mGlu2/3的激活持续减少药物寻求。 然而，这些研究并没有从分子或药物上将mGlu2从3中分离出来，而且有重要意义 当每个受体单独成为靶点时，信号和行为输出的差异就会发生。此外，没有 现有的药理工具可以逆转mGlu2(或3)受体功能的丧失。目前的建议 意义重大，因为这将是第一次单独评估冰毒后mGlu2和mGlu3的表面表达 SA，或者其他。这也将是第一次将性别差异作为此类表达的一个因素。这项建议是 创新源于增加mGlu2(3)表面的新工具(干扰肽)的开发 体内给药后的可用性/功能。最后，我们的目标是开发一种高度翻译的鼻腔 这类多肽的给药途径。我们假设这种方法将允许选择性地恢复 有慢性冰毒暴露史的受试者mGlu2和/或3的表面表达和功能。我们将测试 这一假设的具体目的如下：目标1--评估性别--表面可获得性和功能的差异 MGlu2和mGlu3在PFC中的表达，以及目标2-开发和优化干扰肽的体内递送 这逆转了冰毒后PFC中mGlu2(或3)表面表达和功能的变化。要实现这些目标 为了实现雄心勃勃的目标，我们提议开发创新工具-受体特异性干扰肽。证据- 根据预测，这些多肽将使mGlu2(3)的表面表达/功能正常化，而不需要 传统受体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)受体作为开发新的神经生物学靶点的有效性 治疗，可以用来改善认知表现，降低冰毒复发的脆弱性。

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.