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Hippocampal CCR5/RANTES Elevations in a Rodent Model of Post-Traumatic Stress Disorder: Maraviroc (a CCR5 Antagonist) Increases Corticosterone Levels and Enhances Fear Memory Consolidation

1
Dept. Pharmacology, Pharmacognosy and Botanics. Complutense University of Madrid (UCM)., 28040 Madrid, Spain
2
La Salle Center, Faculty of Agriculture Sciences, Av. Carrera 7. # 179-03 (sede norte, Bogotá, Colombia
3
Psychobiology Dept, UNED (Madrid), 28040, Madrid, Spain
4
Harvard Medical School, MGH, Massachussets General Hospital, 185 Cambridge St Boston MA 02114, Boston, USA
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Cajal Institute (CSIC), 28.002 Madrid, Spain
*
Author to whom correspondence should be addressed.
Actual address: Dpto. Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M). c/Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
Biomolecules 2020, 10(2), 212; https://doi.org/10.3390/biom10020212
Received: 29 December 2019 / Revised: 26 January 2020 / Accepted: 27 January 2020 / Published: 1 February 2020
(This article belongs to the Special Issue The Potential Role of Astrocytes in Memory and Learning Processes)
Background: Contextual fear conditioning (CFC) is a rodent model that induces a high and long-lasting level of conditioning associated with traumatic memory formation; this behavioral paradigm resembles many characteristics of posttraumatic stress disorder (PSTD). Chemokines (chemotactic cytokines) play a known role in neuronal migration and neurodegeneration but their role in cognition is not totally elucidated. Aim: We ascertain whether CCR5/RANTES beta chemokines (hippocampus/prefrontal cortex) could play a role in fear memory consolidation (CFC paradigm). We also evaluated whether chronic stress restraint (21 days of restraint, 6-h/day) could regulate levels of these beta chemokines in CFC-trained rats; fear memory retention was determined taking the level of freezing (context and tone) by the animals as an index of fear memory consolidation 24 h after CFC training session; these chemokines (CCR5/RANTES) and IL-6 levels were measured in the hippocampus and prefrontal cortex of chronically stressed rats, 24 h after CFC post-training, and compared with undisturbed CFC-trained rats (Experiment 1). In Experiment 2, rats received 1 mA of footshock during the CFC training session and fear memory consolidation was evaluated at 12 and 24 h after CFC training sessions. We evaluated whether RANTES levels could be differentially regulated at 12 and 24 h after CFC training; in Experiment 3, maraviroc was administered to rats (i.m: 100 mg/Kg, a CCR5 antagonist) before CFC training. These rats were not subjected to chronic stress restraint. We evaluated whether CCR5 blockade before CFC training could increase corticosterone, RANTES, or IL-6 levels and affects fear memory consolidation in the rats 24-h post-testing compared with vehicle CFC-trained rats. Results: Elevations of CCR5/RANTES chemokine levels in the hippocampus could have contributed to fear memory consolidation (24 h post-training) and chronic stress restraint did not affect these chemokines in the hippocampus; there were no significant differences in CCR5/RANTES levels between stressed and control rats in the prefrontal cortex (Experiment 1). In Experiment 2, hippocampal CCR5/RANTES levels increased and enhanced fear memory consolidation was observed 12 and 24 h after CFC training sessions with 1 mA of footshock. Increased corticosterone and CCR5/RANTES levels, as well as a higher freezing percentage to the context, were found at 24 h CFC post-testing in maraviroc-treated rats as compared to vehicle-treated animals (experiment-3). Conversely, IL-6 is not affected by maraviroc treatment in CFC training. Conclusion. Our findings suggest a role for a hippocampal CCR5/RANTES axis in contextual fear memory consolidation; in fact, RANTES levels increased at 12 and 24 h after CFC training. When CCR5 was blocked by maraviroc before CFC training, RANTES (hippocampus), corticosterone levels, and fear memory consolidation were greater than in vehicle CFC-trained rats 24 h after the CFC session.
Keywords: post traumatic stress disorder; CCR5/RANTES chemokines; neural plasticity; chronic stress restraint; fear learning; neuro repair; neuroinmunology; neuroimmunomodulation. post traumatic stress disorder; CCR5/RANTES chemokines; neural plasticity; chronic stress restraint; fear learning; neuro repair; neuroinmunology; neuroimmunomodulation.
MDPI and ACS Style

Merino, J.J.; Muñetón-Gomez, V.; Muñetón-Gómez, C.; Pérez-Izquierdo, M.Á.; Loscertales, M.; Toledano Gasca, A. Hippocampal CCR5/RANTES Elevations in a Rodent Model of Post-Traumatic Stress Disorder: Maraviroc (a CCR5 Antagonist) Increases Corticosterone Levels and Enhances Fear Memory Consolidation. Biomolecules 2020, 10, 212.

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