Abstract：
Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.
摘要：
阿片类药物使用障碍是一种主要的公共卫生危机，表现为持续的寻药行为和高复发频率。大多数可用的治疗依赖于使用不提供持续症状缓解的小分子靶向阿片受体。心理可塑性原是一类新型的非阿片类药物，对神经元可塑性产生快速和持续的影响，旨在产生治疗益处。ibogalogs是iboga生物碱的合成衍生物，缺乏致幻或不良副作用。在目前的研究中,我们研究了DM506的治疗潜力，这是一种缺乏任何心脏毒性或致幻作用的新型ibogalog，在海洛因自我管理后的线索诱导的寻求行为中。在40mg/kg的单次全身剂量下，在海洛因自我给药后的禁欲第1天（AD1），DM506显着降低了雄性和雌性大鼠的提示诱导的寻求。在AD14重新测试提示诱导的寻求后，我们发现接受DM506的男性继续显示提示诱导的寻求减少，在女性中没有观察到的效果。由于有证据表明迷幻药会影响补品GABA电流，和阿片样物质和精神病原介导的神经适应在内侧前额叶皮质（PrL）的基础上，其功能作用，我们对急性应用或长期孵育DM506的未用药大鼠的PrL切片进行了膜片钳记录.在用DM506孵育2小时的切片中,TonicGABA电流降低。qPCR分析未显示在AD1接受媒介物或DM506的海洛因和盐水自给动物中AD14时GABAA受体α和δ亚基的mRNA水平有任何差异。总的来说,我们的数据表明,DM506减弱了线索诱导的海洛因寻找,并抑制了前边缘皮层的补品GABA电流.
