The α2a-adrenergic receptor (α2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.

中文翻译：

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压力诱导的可卡因条件性位置偏好的恢复需要α2A-肾上腺素能异质受体。

α2a-肾上腺素能受体 (α2a-AR) 激动剂胍法辛已被研究作为物质使用障碍的潜在治疗方法。虽然在动物模型中减少压力引起的可卡因寻求恢复和人类研究中压力引起的渴望，但据报道胍法辛可以降低复发率。虽然胍法辛与 α2a-AR 自身受体结合，但它也会激活终纹床核 (BNST) 中的兴奋性 Gi 偶联异源受体，BNST 是驱动压力诱发复发的关键大脑区域。因此，BNST α2a-AR 异质受体信号可能会降低胍法辛的有益功效。我们旨在确定 α2a-AR 异源受体和 BNST Gi-GPCR 信号在压力诱导的可卡因条件性位置偏好 (CPP) 恢复中的作用以及低剂量胍法辛对 BNST 活性和压力诱导的恢复的影响。我们使用遗传删除策略和可卡因 CPP 程序来首先定义 α2a-AR 异源受体对压力诱导恢复的贡献。接下来，我们使用由设计药物 (Gi-DREADD) 方法专门激活的 Gi 偶联设计受体模拟了 BNST Gi 偶联的 α2a-AR 异质受体信号传导。最后，我们评估了低剂量胍法辛对 BNST cFOS 免疫反应性和应激诱导恢复的影响。我们表明，α2a-AR 异质受体缺失会破坏应激诱导的恢复，并且 BNST Gi-DREADD 激活足以诱导恢复。重要的是，我们发现低剂量胍法辛不会增加 BNST 活性，但可以防止压力引起的恢复。我们的研究结果证明了 α2a-AR 异质受体和 BNST Gi-GPCR 信号传导在压力诱导的可卡因 CPP 恢复中的作用，并提供了对剂量对胍法辛作为压力诱导的可卡因使用复发治疗的疗效的影响的见解。