Abstract
Post-traumatic stress disorder (PTSD) is a common anxiety mental disorder and can be manifested after exposure to a real or perceived life-threatening event. Increased noradrenaline and adrenaline in plasma and urine have been documented in PTSD. Dopamine-β-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and consequently, DBH inhibition reduces catecholamines. Our aim was to evaluate if nepicastat treatment decreases PTSD signs in an animal model. Wild-type (129x1/SvJ) female mice were submitted to PTSD induction protocol. DBH-inhibitor nepicastat (30 mg/kg) or vehicle (0.2% HPMC) were administered once daily since day 0 until day 7 or 12. The percentage of freezing was calculated on days 0, 1, 2, and 7, and behavioral tests were performed. Quantification of nepicastat in plasma and DBH activity in the adrenal gland was evaluated. Catecholamines were quantified by HPLC with electrochemical detection. mRNA expression of Npas4 and Bdnf in hippocampus was evaluated by qPCR.Mice in the PTSD-group and treated with nepicastat showed a decrease in freezing, and an increase in the time spent and entries in open arms in elevated plus maze test. In mice treated with nepicastat, adrenal gland DBH activity was decreased, and catecholamines were also decreased in plasma and tissues. On day 7, in mice treated with nepicastat, there was an increase of Npas4 and Bdnf mRNA expression in the hippocampus.In conclusion, DBH inhibitor nepicastat has an effect consistent with a decrease in the persistence of traumatic memories and anxiety-like behavior in this PTSD mice model. The disruption of traumatic memories through interference with the formation, consolidation, retrieval, and/or expression processes may be important to decrease PTSD symptoms and signs. The increase in Npas4 and Bdnf mRNA expression in the hippocampus may be important to develop a weaker traumatic contextual memory after nepicastat treatment.
Highlights
Previous research discovered that when a stored memory is recalled, it becomes susceptible to disruption for a short period (Nader et al, 2000; Alberini, 2005)
The time spent in open arms (t(22) = 2.68, p = 0.0141, Cohen’s d = 1.06; Figure 3A), open arm entries (t(22) = 3.97, p = 0.0007, Cohen’s d = 1.48; Figure 3B), and the total number of arm entries (t(22) = 4.61, p = 0.0001, Cohen’s d = 1.90; Figure 3C) were significantly increased in mice in the post-traumatic stress disorder (PTSD)-group and treated with nepicastat when compared to mice treated with vehicle
After exposure to a traumatic event, PTSD is more likely to develop in females than in males since estrogen promotes catecholamine production (Breslau et al, 1999; McDermott et al, 2015)
Summary
Previous research discovered that when a stored memory is recalled, it becomes susceptible to disruption for a short period (Nader et al, 2000; Alberini, 2005). This finding suggests that it may be possible to weaken or even erase memories of traumatic experiences that have resulted in post-traumatic stress disorder (PTSD). Memories of negative emotional events tend to last a long period, frequently remaining detailed and vivid (Brown and Kulik, 1977; Kensinger et al, 2006). Elucidating the mechanisms behind the recall and persistence of negative emotional memories is crucial for both basic cognitive science and clinical psychopathology research
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