Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Neurochem. 2023 Jan;164(2):143-157. doi: 10.1111/jnc.15706. Epub 2022 Oct 24.
Glutamate NMDA receptors (NMDARs) in the nucleus accumbens (NAc) are critically involved in drug dependence and reward. α2δ-1 is a newly discovered NMDAR-interacting protein that promotes synaptic trafficking of NMDARs independently of its conventional role as a calcium channel subunit. However, it remains unclear how repeated opioid exposure affects synaptic NMDAR activity and α2δ-1-NMDAR interaction in the NAc. In this study, whole-cell patch-clamp recordings showed that repeated treatment with morphine in mice markedly increased the NMDAR-mediated frequency of miniature excitatory postsynaptic currents (mEPSCs) and amplitude of puff NMDAR currents in medium spiny neurons in the NAc core region. Morphine treatment significantly increased the physical interaction of α2δ-1 with GluN1 and their synaptic trafficking in the NAc. In Cacna2d1 knockout mice, repeated treatment with morphine failed to increase the frequency of mEPSCs and amplitude of puff NMDAR currents in the NAc core. Furthermore, inhibition of α2δ-1 with gabapentin or disruption of the α2δ-1-NMDAR interaction with the α2δ-1 C terminus-interfering peptide blocked the morphine-elevated frequency of mEPSCs and amplitude of puff NMDAR currents in the NAc core. Correspondingly, systemically administered gabapentin, Cacna2d1 ablation, or microinjection of the α2δ-1 C terminus-interfering peptide into the NAc core attenuated morphine-induced conditioned place preference and locomotor sensitization. Our study reveals that repeated opioid exposure strengthens presynaptic and postsynaptic NMDAR activity in the NAc via α2δ-1. The α2δ-1-bound NMDARs in the NAc have a key function in the rewarding effect of opioids and could be targeted for treating opioid use disorder and addiction.
谷氨酸 NMDA 受体（NMDARs）在伏隔核（NAc）中对于药物依赖和奖赏至关重要。α2δ-1 是一种新发现的 NMDAR 相互作用蛋白，它独立于其作为钙通道亚基的传统作用促进 NMDAR 的突触转运。然而，反复阿片类药物暴露如何影响 NAc 中的突触 NMDAR 活性和 α2δ-1-NMDAR 相互作用仍不清楚。在这项研究中，全细胞膜片钳记录显示，在小鼠中反复给予吗啡处理显著增加了 NAc 核心区中型多棘神经元中 NMDAR 介导的微小兴奋性突触后电流（mEPSCs）的频率和 puff NMDAR 电流的幅度。吗啡处理显著增加了 α2δ-1 与 GluN1 的物理相互作用及其在 NAc 中的突触转运。在 Cacna2d1 敲除小鼠中，反复给予吗啡处理未能增加 NAc 核心区 mEPSCs 的频率和 puff NMDAR 电流的幅度。此外，用加巴喷丁抑制 α2δ-1 或用 α2δ-1 C 端干扰肽破坏 α2δ-1-NMDAR 相互作用阻断了 NAc 核心区吗啡诱导的 mEPSCs 频率和 puff NMDAR 电流幅度的升高。相应地，系统给予加巴喷丁、Cacna2d1 消融或将 α2δ-1 C 端干扰肽微注射到 NAc 核心区减弱了吗啡引起的条件性位置偏好和运动敏化。我们的研究揭示了反复阿片类药物暴露通过 α2δ-1 增强了 NAc 中的突触前和突触后 NMDAR 活性。NAc 中与 α2δ-1 结合的 NMDAR 在阿片类药物的奖赏效应中具有关键作用，可作为治疗阿片类药物使用障碍和成瘾的靶点。
