Rice Onarae V, Ashby Charles R, Dixon Clark, Laurenzo William, Hayden Jason, Song Rui, Li Jin, Tiwari Amit K, Gardner Eliot L
Psychology Department, Neuroscience Program, Furman University, 3300 Poinsett Highway, Greenville, South Carolina.
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, New York.
Synapse. 2018 Aug;72(8):e22035. doi: 10.1002/syn.22035. Epub 2018 Jun 7.
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric syndrome that occurs in individuals exposed to extremely threatening or traumatic events. In both animals and humans, dopamine (DA) function appears to be dysregulated in brain areas involved in the conditioned fear response(s) that underlie PTSD. In this study, we determined the effect of the selective DA D receptor antagonists YQA14A (6.25, 12.5 and 25 mg/kg i.p.) and SB-277011A (6 mg/kg i.p.) on tone-induced fear (assessed by measuring freeze time) in a modified version of the single-prolonged stress (SPS) model of PTSD in adult male Sprague-Dawley rats. Rats pretreated with vehicle and then subjected to restraint stress, forced swim and random foot shock (SPS) in the presence of a distinctive tone, displayed a significantly increased tone-induced contextual freeze time and fecal pellet mass following re-exposure to the tone. Rats pretreated with a single i.p. injection of 6.25 or 12.5 mg/kg of YQA14 or 6 mg/kg of SB-277011A showed significantly attenuated contextual freeze time in the presence of the tone when tested 14 days after exposure to SPS. Overall, our results indicate that selectively antagonizing DA D receptors significantly decreases freezing time caused by an environment previously associated with stress. If our findings can be extrapolated to humans with PTSD, they suggest that DA D receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD.
创伤后应激障碍（PTSD）是一种使人衰弱的精神综合征，发生于经历过极端威胁性或创伤性事件的个体。在动物和人类中，多巴胺（DA）功能在参与构成PTSD基础的条件性恐惧反应的脑区似乎失调。在本研究中，我们在成年雄性Sprague-Dawley大鼠创伤后应激障碍的单延长应激（SPS）模型的改良版中，确定了选择性DA D受体拮抗剂YQA14A（6.25、12.5和25mg/kg腹腔注射）和SB-277011A（6mg/kg腹腔注射）对音调诱发恐惧（通过测量静止时间评估）的影响。用赋形剂预处理后，然后在独特音调存在的情况下接受束缚应激、强迫游泳和随机足部电击（SPS）的大鼠，在再次暴露于该音调后，表现出显著增加的音调诱发情境静止时间和粪便颗粒量。在暴露于SPS后14天进行测试时，单次腹腔注射6.25或12.5mg/kg的YQA14或6mg/kg的SB-277011A预处理的大鼠，在音调存在的情况下，表现出显著减弱的情境静止时间。总体而言，我们的结果表明，选择性拮抗DA D受体会显著减少由先前与应激相关的环境引起的静止时间。如果我们的发现可以外推至患有PTSD的人类，那么表明DA D受体可能在PTSD的病理生理学中起作用，并且可能对PTSD的临床管理具有治疗效用。
