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

Raquel Martinho; Gabriela Correia; Rafaela Seixas; Ana Oliveira; Soraia Silva; Paula Serrão; Carlos Fernandes-Lopes; Cristina Costa; Mónica Moreira-Rodrigues

doi:10.3389/fnmol.2021.745219

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

Front Mol Neurosci. 2021 Sep 24:14:745219. doi: 10.3389/fnmol.2021.745219. eCollection 2021.

Authors

Raquel Martinho^{1

2}, Gabriela Correia^{1

2}, Rafaela Seixas^{1

2}, Ana Oliveira^{1

2}, Soraia Silva^{1

2}, Paula Serrão^{2

3}, Carlos Fernandes-Lopes⁴, Cristina Costa⁴, Mónica Moreira-Rodrigues^{1

2}

Affiliations

¹ Laboratory of General Physiology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS/UP), Porto, Portugal.
² Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal.
³ Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal.
⁴ Department of Research, BIAL, Porto, Portugal.

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.

Keywords: contextual traumatic memory; dopamine β-hydroxylase; nepicastat; noradrenaline; post-traumatic stress disorder.