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

Abstract

The processes by which fear memory is encoded, consolidated, and re-consolidated are extremely complex and appear to require the release of stress hormones, especially adrenaline (AD). AD improves contextual fear memory, acting specifically on peripheral β2-adrenoceptors. Propranolol (peripheral and central β-adrenoceptor antagonist) treatment was shown to prevent post-traumatic stress disorder (PTSD) development and reduce its symptoms. However, propranolol has several side effects. Thus, we aimed to evaluate if sotalol (a peripheral β-adrenoceptor antagonist) treatment interferes with retrieval, expression, and/or reconsolidation of traumatic memories in a validated mice model that mimics the signs/symptoms of PTSD, thus intending to decrease them. Female mice were induced with PTSD following an established protocol. Sotalol (2.0 mg/kg) or vehicle were administered on days 2, 7, and 14. The percentage of freezing was calculated, and behavioral tests were carried out. Catecholamines in plasma were quantified by HPLC with electrochemical detection. Quantitative real-time polymerase chain reaction (qPCR) was used to evaluate mRNA expression of NR4A family genes in hippocampus. Following the submission of the animals to the same aversive context on days 2, 7, and 14, sotalol-treated mice exhibited significant less freezing behavior. In the elevated plus-maze test, the time spent and number of entries in the open arms, and total arm entries were increased in sotalol-treated mice. Also, the light-dark transition test revealed higher time spent, number of transitions to the light, and total number of transitions in sotalol-treated mice. Moreover, plasma AD was significantly decreased in sotalol-treated mice. On day 14, sotalol-treated mice exhibited a decrease in mRNA expression of Nr4a1 in the hippocampus. In conclusion, in PTSD mice model, sotalol appears to decrease traumatic memories and anxiety-like behavior, probably due to a decrease in peripheral adrenergic activity, which influences traumatic memories. The effects of sotalol upon re-exposure to the traumatic context may be consistent with interference in the retrieval, expression, and/or reconsolidation processes of contextual traumatic memory, resulting in a long-term reduction of PTSD symptoms and signs. The decreased Nr4a1 mRNA expression in the hippocampal formation may be crucial for these mice to develop diminished traumatic contextual memories after sotalol therapy in PTSD.

Glucose may Contribute to Retrieval and Reconsolidation of Contextual Fear Memory Through Hippocampal Nr4a3 and Bdnf mRNA Expression and May Act Synergically with Adrenaline

“…We propose that this happens due to an increase in glucose uptake in the CNS. In addition, our group has shown a possible involvement of the Nr4a gene family in the persistence of PTSD symptoms and signs [ 25 ], verifying a significant downregulation of the Nr4a1 gene expression in the hippocampus of WT mice administrated with sotalol, a peripheral β-adrenoceptor antagonist, when compared to vehicle-treated mice [ 54 ].…”

Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder

“…These data show that hippocampus genes may play a role in the modulation of traumatic contextual memories in PTSD animals: Nr4a family genes in sotalol treatment ( Martinho et al, 2022 ), and Npas4 and Bdnf genes in nepicastat treatment ( Martinho et al, 2021 ; Moreira-Rodrigues and Grubisha, 2022 ; Abumaria et al, 2023 ). This difference may also be related to different treatment regimens.…”

“…Considering these facts, administration of the peripheral β-AR antagonist, sotalol, could overcome the unwanted central effects of propranolol. In fact, PTSD animals treated with sotalol exhibited decreased traumatic contextual memories, anxiety-like behaviors, and plasma catecholamines compared to vehicle-treated animals ( Martinho et al, 2022 ). These effects of sotalol most probably result from a reduction of catecholamine effects in peripheral β-ARs leading to attenuation of the sympathetic autonomic overactivity, which indirectly down-modulates traumatic contextual memories ( Martinho et al, 2022 ).…”

“…In fact, PTSD animals treated with sotalol exhibited decreased traumatic contextual memories, anxiety-like behaviors, and plasma catecholamines compared to vehicle-treated animals ( Martinho et al, 2022 ). These effects of sotalol most probably result from a reduction of catecholamine effects in peripheral β-ARs leading to attenuation of the sympathetic autonomic overactivity, which indirectly down-modulates traumatic contextual memories ( Martinho et al, 2022 ). With the data available so far, one can only speculate about the involvement of the sympathetic-induced vagal nerve drive and/or glucose release theories ( Clark et al, 1999 ; Miyashita and Williams, 2004 , 2006 ; Chen and Williams, 2012 ; Gold, 2014 ) to explain the results showing decreases in Nr4a1 mRNA transcripts in the hippocampus of sotalol-treated mice ( Martinho et al, 2022 ).…”

“…These effects of sotalol most probably result from a reduction of catecholamine effects in peripheral β-ARs leading to attenuation of the sympathetic autonomic overactivity, which indirectly down-modulates traumatic contextual memories ( Martinho et al, 2022 ). With the data available so far, one can only speculate about the involvement of the sympathetic-induced vagal nerve drive and/or glucose release theories ( Clark et al, 1999 ; Miyashita and Williams, 2004 , 2006 ; Chen and Williams, 2012 ; Gold, 2014 ) to explain the results showing decreases in Nr4a1 mRNA transcripts in the hippocampus of sotalol-treated mice ( Martinho et al, 2022 ). Our hypothesis is that sotalol may be repurposed as a possible alternative to SSIRs for PTSD treatment, especially in patients with peripheral sympathetic hyperactivity.…”