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.

Keywords: contextual traumatic memory; peripheral β-adrenoceptor antagonist; post-traumatic stress disorder; sotalol; β-adrenoceptors.

FIGURE 1

Schematic representation of the experimental design: treatments, behavioral protocols, and samples collection. (A) First experimental protocol and (B) second experimental protocol.

FIGURE 2

(A, B) Shock responsivity and (C–G) freezing behavior during induction of post-traumatic stress disorder (PTSD) on (A, C) day 0, (B, D) day 1, (E) day 2, (F) day 7, and (G) day 14. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. Values are means ± SEM of 13 mice per group. *, treatment and time effect with two-way repeated measures ANOVA (p < 0.05). †, interaction with two-way repeated measures ANOVA (p < 0.05).

FIGURE 3

(A) Time spent in open arms, (B) open arm entries, (C) time spent in closed arms, and (D) total arm entries of the elevated plus-maze test (EPMT), on day 15 after post-traumatic stress disorder (PTSD) induction. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. Values are means ± SEM of 6-7 mice per group. *, significantly different from correspondent values in vehicle-treated PTSD mice (p ˂ 0.05).

FIGURE 4

(A) Time spent in the light compartment, (B) number of transitions to the light compartment, and (C) total number of transitions between light and dark compartments of light-dark transition test (LDTT), on day 16 after post-traumatic stress disorder (PTSD) induction. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. Values are means ± SEM of 6-7 mice per group. *, significantly different from correspondent values in vehicle-treated PTSD mice (p ˂ 0.05).

FIGURE 5

(A) Total distance travelled, and number of (B) squares crossed, (C) entries in the center, and (D) entries in the periphery in the open field test (OFT), on day 17 after post-traumatic stress disorder (PTSD) induction. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. Values are means ± SEM of 6-7 mice per group.

FIGURE 6

Concentration of plasma (A) dopamine (DA), (B) noradrenaline (NA), and (C) adrenaline (AD) after post-traumatic stress disorder (PTSD) induction (day 14). Values are means ± SEM of 6-7 mice per group. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. *, significantly different from correspondent values in vehicle-treated PTSD mice (p ˂ 0.05).

FIGURE 7

Concentration of adrenal gland (A) dopamine (DA), (B) noradrenaline (NA), and (C) adrenaline (AD) after post-traumatic stress disorder (PTSD) induction (day 14). Values are means ± SEM of 6-7 mice per group. Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice.

FIGURE 8

Hippocampus mRNA expression of (A) Nuclear receptor 4 (Nr4) a1; (B) Nr4a2, and (C) Nr4a3 on day 14 of post-traumatic stress disorder (PTSD) induction. Values are means ± SEM of 6-7 mice per group. Results of mRNA are expressed as arbitrary units (AUs) after normalization for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Veh, vehicle-treated PTSD mice; Sotalol, sotalol-treated PTSD mice. *, significantly different from correspondent values in vehicle-treated PTSD mice (p ˂ 0.05).