Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

滥用药物会导致前额皮质（PFC）和相关区域发生变化，从而损害对药物寻求的抑制控制。在消退学习过程中打破与药物相关的线索和奖励的提供之间的偶然性可以减少复发。迷走神经刺激（VNS）此前已被证明可以增强消退学习并减少药物寻求。在这里，我们确定了 VNS 介导的脑源性神经营养因子 (BDNF) 释放对经过自我注射可卡因训练的雄性大鼠的灭绝和提示诱导恢复的影响。将 10 天的消退训练与 VNS 结合起来可以促进消退并减少恢复期间的寻求药物行为。通过酶联免疫吸附试验测定，接受 VNS 单次消退训练的大鼠内侧 PFC 中 BDNF 水平升高。在灭绝过程中，通过 TrkB 拮抗剂 ANA-12 系统性阻断原肌球蛋白受体激酶 B (TrkB) 受体，可降低 VNS 对灭绝和恢复的影响。脑切片中的全细胞记录显示，自我施用可卡因会导致边缘下皮层 (IL) 第 5 层锥体神经元中 AMPA 和 NMDA 受体介导的电流比率发生变化。将消退与 VNS 配对，通过增强 AMPAR 电流来逆转可卡因诱导的谷氨酸能传递变化，而这种效应被 ANA-12 阻断。我们的研究表明，VNS 通过逆转药物诱导的 IL 中突触 AMPA 受体的变化来巩固寻药行为的消退，并且通过在消退过程中阻断 TrkB 受体来消除这种效应，强调了 VNS 在寻药行为中发挥治疗作用的潜在机制。瘾。