Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA.
Transl Psychiatry. 2024 Jul 12;14(1):283. doi: 10.1038/s41398-024-03001-y.
Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERβ in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERβ agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERβ across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERβ agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERβ expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERβ's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERβ expression across several different brain regions showed that females only had greater expression of ERβ in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERβ agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.
复吸是治疗阿片类药物使用障碍 (OUD) 的主要挑战。复吸可能由多种因素引起，包括接触药物条件线索。由于消退记忆召回 (EMR) 缺陷，确定成功的治疗方法来减轻线索诱发的复吸一直具有挑战性。此前，外侧杏仁核 (BLA) 中的雌二醇 (E2) 信号抑制会损害海洛因线索 EMR。BLA 雌激素受体 (ER) 以性别特异性方式拮抗以这种方式复制了这种作用，即阻断雄性中的 ERα，而阻断雌性中的 ERβ，会损害 EMR。然而，尚不清楚 BLA 或全身的 E2 信号增加是否会增强海洛因线索 EMR。我们假设 ERβ 激动剂会以性别和区域特异性的方式增强海洛因线索 EMR。为了确定 E2 信号改善 EMR 的能力，我们在几个转化设计的实验中对 ERβ 进行了药理学操作。首先，雄性和雌性大鼠进行海洛因或蔗糖自我给药。接下来，在线索消退期间，我们给予二芳基丙腈 (DPN，一种 ERβ 激动剂)，并在开放场中测试焦虑样行为。随后，我们在线索诱导的复吸测试中评估 EMR，最后，测量几个脑区的 ERβ 表达。在所有实验中，雌性大鼠摄入的海洛因和蔗糖均多于雄性大鼠，并且在海洛因线索消退期间反应更大。仅在雌性大鼠中，BLA 中的 DPN 给药增强了 EMR，这是由 ERβ 对记忆巩固的影响驱动的。有趣的是，然而，系统给予 DPN 可改善几种不同测试中海洛因线索的 EMR，但不会影响蔗糖线索的 EMR。几种不同脑区的 ERβ 表达的免疫组织化学分析表明，只有雌性大鼠的 BLA 基底核中的 ERβ 表达更高。在这里，在几个临床前实验中，我们证明了 ERβ 激动剂增强了海洛因线索的 EMR，并且在对抗线索诱导的复吸方面具有潜在的应用价值。
