Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

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.

Repeated Oral Administration of Flavan-3-ols Induces Browning in Mice Adipose Tissues through Sympathetic Nerve Activation

“…In clinical analysis, the correlation between sympathetic nerve activation and plasma or urine levels is controversial. In contrast, the correlation between them was verified in various rodent stress models [38][39][40]. As described before, sympathetic hyperactivity following a single oral dose of FLs may occur as a stress response [41].…”

“…Determination of urinary CAs has been used to assess SNS activity induced by stressors in mammals [54]. Especially, the correlation between the activity of SNS and the level of plasma or urine CAs was verified in rodent stress models, such as social defeat [38], hypothermia [39], or PTSD models [40]. Oral administration of FLs likely activate SNS because they are considered stressors in rodent models.…”

Sotalol Treatment may Interfere With Retrieval, Expression, and/or Reconsolidation Processes Thus Disrupting Traumatic Memories in a Post-Traumatic Stress Disorder Mice Model

“…On day 15, the EPMT was performed (Figure 1B), as formerly reported (Pellow et al, 1985;Fertan et al, 2019;Martinho et al, 2020;Gasparyan et al, 2021;Martinho et al, 2021). The experimental device was positioned 60 cm above the floor and comprised two open arms (40 × 10 cm) and two enclosed arms (40 × 10 cm with 20 cm high walls), displaying a total of four arms delimiting a central area of 5 cm 2 and arranged at right angles with equal arms facing each other.…”

“…PTSD research is highly dependent on several animal models that have originated from the use of various forms of trauma experiences ( Pynoos et al, 1996 ). The PTSD mice model chosen to be carried out in the present study is based on the concept that submission to electrical shocks leads the animals to develop PTSD’s pathophysiological processes and earliest complex symptoms and signs of the pathology, such as enhanced contextual traumatic memory and anxiety-like behavior ( Li et al, 2006 ; Zhang et al, 2012 ; Martinho et al, 2020 ; Martinho et al, 2021 ). Previously, we and others reported that the exposure to multiple foot shocks is efficient to replicate the traumatic episode in this model ( Li et al, 2006 ; Zhang et al, 2012 ; Verma et al, 2016 ; Martinho et al, 2020 ).…”

“…Despite the relation between AD and contextual traumatic memories’ persistence ( Alves et al, 2016 ; Oliveira et al, 2018 ; Martinho et al, 2020 ; Martinho et al, 2021 ), AD does not pass the blood-brain barrier and is known to have mainly peripheral actions. There are two theories concerning the role of this hormone in fear memory enhancement.…”