PDF(Pubmed)
Abstract：
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.
摘要：
返回使用,或复发，是治疗阿片类药物使用障碍（OUD）的主要挑战。复发可以由几个因素引起，包括暴露于药物条件的线索。确定成功的治疗方法以减轻提示引起的复发一直具有挑战性，也许是由于灭绝记忆回忆(EMR)缺陷。以前,基底外侧杏仁核（BLA）中雌二醇（E2）信号的抑制受损的海洛因提示EMR。通过以性别特异性方式拮抗BLA雌激素受体（ER），从而阻断男性的ERα，但是女性的ERβ，受损的EMR。然而,目前尚不清楚E2信号是否增加，在BLA或系统上，增强海洛因提示EMR。我们假设ERβ激动作用会以性别和地区特异性方式增强海洛因提示EMR。为了确定E2信令的容量以提高EMR，我们在几个翻译设计的实验中对ERβ进行了药理学处理。首先,雄性和雌性大鼠获得海洛因或蔗糖自我给药。接下来,在一个线索灭绝的过程中，我们服用了二芳基丙腈(DPN，ERβ激动剂）并在开阔的视野中测试了焦虑样行为。随后，我们在提示诱导的恢复测试中评估了EMR，最后,在几个脑区测量ERβ表达。在所有实验中，女性比男性服用更多的海洛因和蔗糖，并且在海洛因提示灭绝期间反应更大。在BLA中施用DPN仅增强女性的EMR，由ERβ对内存整合的影响驱动。有趣的是,然而,在几种不同的测试中，系统性DPN给药改善了男女海洛因线索的EMR，但不影响蔗糖提示EMR。对几个不同大脑区域的ERβ表达的免疫组织化学分析表明，雌性仅在BLA的基底核中有较高的ERβ表达。这里,在几个临床前实验中，我们证明ERβ激动可增强海洛因提示EMR,并且在对抗提示引起的复发方面具有潜在效用.
