Fear-related anxiety disorders, such as social phobia and post-traumatic stress disorder, are partly explained by an uncontrollable state of fear. An emerging literature suggests dopamine receptor-1 (D₁ receptor) in the amygdala is involved in the regulation of fear memory. An early study has reported that amygdaloid D₁ receptor (D₁R) is not coupled to the classic cAMP-dependent signal transduction. Here, we investigated whether SKF83959, a typical D₁R agonist that mainly activates a D₁-like receptor-dependent phosphatidylinositol (PI) signal pathway, facilitates fear extinction and reduces the return of extinguished fear. Interestingly, long-term loss of fearful memories can be induced through a combination of SKF83959 (1 mg/kg/day, i.p., once daily for one week) pharmacotherapy and extinction training. Furthermore, sub-chronic administration of SKF83959 after fear conditioning reduced fear renewal and reinstatement in the mice. We found that the activation D₁R and PI signaling in the amygdala was responsible for the effect of SKF83959 on fear extinction. Additionally, SKF83959 significantly promoted the elevation of brain-derived neurotrophic factor (BDNF) expression, possibly by the cAMP response element binding protein (CREB) -directed gene transcription. Given the beneficial effects on extinction, SKF83959 may emerge as a candidate pharmacological approach for improving cognitive-behavioral therapy on fear-related anxiety disorders.

与恐惧相关的焦虑症，例如社交恐惧症和创伤后应激障碍，部分原因是无法控制的恐惧状态。一项新兴文献表明，杏仁核中的多巴胺受体-1（D ₁受体）参与了恐惧记忆的调节。一项早期研究报告称，杏仁核素 D ₁受体 (D ₁ R) 未与经典的 cAMP 依赖性信号转导偶联。在这里，我们研究了 SKF83959，一种典型的 D ₁ R 激动剂，主要激活 D ₁受体依赖性磷脂酰肌醇 (PI) 信号通路，促进恐惧消退并减少已熄灭的恐惧的回归。有趣的是，通过结合 SKF83959（1 毫克/公斤/天，腹腔注射，每天一次，持续一周）药物疗法和灭绝训练，可以诱导长期丧失可怕的记忆。此外，在恐惧条件反射后亚慢性给药 SKF83959 减少了小鼠的恐惧更新和恢复。我们发现激活 D ₁杏仁核中的 R 和 PI 信号是 SKF83959 对恐惧消退的影响的原因。此外，SKF83959 显着促进脑源性神经营养因子 (BDNF) 表达的升高，可能是通过 cAMP 反应元件结合蛋白 (CREB) 指导的基因转录。鉴于对灭绝的有益影响，SKF83959 可能会成为改善恐惧相关焦虑症的认知行为疗法的候选药理学方法。