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. 2022 Oct 29:26:100542.
doi: 10.1016/j.bbih.2022.100542. eCollection 2022 Dec.

MDMA administration attenuates hippocampal IL-β immunoreactivity and subsequent stress-enhanced fear learning: An animal model of PTSD

Shveta V Parekh  1 , Lydia O Adams  1 , Gillian A Barkell  1 , Donald T Lysle  1
Affiliations

MDMA administration attenuates hippocampal IL-β immunoreactivity and subsequent stress-enhanced fear learning: An animal model of PTSD

Shveta V Parekh et al. Brain Behav Immun Health. .

Abstract

Post-traumatic stress disorder (PTSD) is a devastating disorder that involves maladaptive changes in immune status. Using the stress-enhanced fear learning (SEFL) paradigm, an animal model of PTSD, our laboratory has demonstrated increased pro-inflammatory cytokine immunoreactivity in the hippocampus following severe stress. Recent clinical trials have demonstrated 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy as an effective novel treatment for PTSD. Interestingly, MDMA has been shown to have an immunosuppressive effect in both pre-clinical and clinical studies. Therefore, we predict MDMA administration may attenuate SEFL, in part, due to an immunosuppressive mechanism. The current studies test the hypothesis that MDMA is capable of attenuating SEFL and inducing alterations in expression of TNF-α, IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte specific marker, and ionized calcium-binding adapter molecule -1 (IBA-1), a microglial specific marker, in the dorsal hippocampus (DH) following a severe stressor in male animals. To this end, experiment 1 determined the effect of MDMA administration 0, 24, and 48 h following a severe foot shock stressor on SEFL. We identified that MDMA administration significantly attenuated SEFL. Subsequently, experiment 2 determined the effect of MDMA administration following a severe stressor on the expression of TNF-α, IL-1β, GFAP, and IBA-1 in the DH. We found that MDMA administration significantly attenuated stress-induced IL-1β and stress-reduced IBA-1 but had no effect on TNF-α or GFAP. Overall, these results support the hypothesis that MDMA blocks SEFL through an immunosuppressive mechanism and supports the use of MDMA as a potential therapeutic agent for those experiencing this disorder. Together, these experiments are the first to examine the effect of MDMA in the SEFL model and these data contribute significantly towards the clinical PTSD findings.

Keywords: 3,4-Methylenedioxymethamphetamine (MDMA); Astrocyte; Cytokine; Hippocampus; Interleukin-1β (IL-β); Microglia; Post-traumatic stress disorder (PTSD); Stress-enhanced fear learning (SEFL); Tumor necrosis factor-α (TNF-α).

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

Fig. 1
Fig. 1
MDMA prevents the development of stress-enhanced fear learning. Experimental timeline (A). MDMA significantly attenuated stress-enhanced fear learning (N = 59, n = 15–16) (B). *, statistically significant difference relative to respective control. Error bars indicate SEM.
Fig. 2
Fig. 2
Timeline of Immunohistochemistry Experiments. Experimental timeline for tissue collection in Fig. 3, Fig. 4, Fig. 5, Fig. 6 (A). Paxinos and Watson schematic depicting bilateral image acquisition location for the dentate gyrus of the dorsal hippocampus in Fig. 3, Fig. 4, Fig. 5, Fig. 6 (B).
Fig. 3
Fig. 3
MDMA decreases IL-1β immunoreactivity and cell counts in the dentate gyrus of the dorsal hippocampus following severe stress. Quantification of positive fluorescence stain of IL-1β (Alexa-488) (A). Quantification of IL-1β positive cells (B) (N = 29, n = 7–8). Representative images ( × 20) for saline and MDMA animals taken within the DG of the DH (C). *, statistically significant difference relative to respective control. Error bars indicate SEM.
Fig. 4
Fig. 4
MDMA has no effect on TNF-α immunoreactivity and cell counts in the dentate gyrus of the dorsal hippocampus following severe stress. Quantification of positive fluorescence stain of TNF-α (Alexa-488) (A). Quantification of TNF-α positive cells (B) (N = 30, n = 7–8). Representative images ( × 20) for saline and MDMA animals taken within the DG of the DH. (C). *, statistically significant difference relative to respective control. Error bars indicate SEM.
Fig. 5
Fig. 5
MDMA has no effect on GFAP immunoreactivity and cell counts in the dentate gyrus of the dorsal hippocampus following severe stress. Quantification of positive fluorescence stain of GFAP (Alexa 594) (A). Quantification of GFAP positive cells (B) (N = 31, n = 7–8). Representative images ( × 20) for saline and MDMA animals taken within the DG of the DH. (C). *, statistically significant difference relative to respective control. Error bars indicate SEM.
Fig. 6
Fig. 6
MDMA has a marginal effect on IBA-1 immunoreactivity and attenuates the reduction of cell counts in the dentate gyrus of the dorsal hippocampus following severe stress. Quantification of positive fluorescence stain of IBA-1 (Alexa-488) (A). Quantification of IBA-1 positive cells (B) (N = 30, n = 7–8). Representative images ( × 20) for saline and MDMA animals taken within the DG of the DH. (C). *, statistically significant difference relative to respective control. Error bars indicate SEM.
Fig. 7
Fig. 7
Schematic of experimental results and candidate mechanisms. Results from experiment 1 indicate severe shock leads to the development of enhanced fear learning and MDMA blocks the development of enhanced fear learning (A, B). Results from experiment 2 indicate that severe shock increases IL-1β immunoreactivity and decreases microglial counts in the dorsal hippocampus (C, E). Administration of MDMA blocks the stress-induced increase of IL-1β and decrease of microglia in the dorsal hippocampus (D, F). Overall, we believe that blocking stress-induced increase of IL-1β and decrease of microglia may act as neuroimmune mechanisms by which MDMA prevents the development of enhanced fear learning (G, H). Created with BioRender.com.
See this image and copyright information in PMC

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References

    1. Abad S., Ramon-Duaso C., Lopez-Arnau R., Folch J., Pubill D., Camarasa J., Camins A., Escubedo E. Effects of MDMA on neuroplasticity, amyloid burden and phospho-tau expression in APPswe/PS1dE9 mice. J. Psychopharmacol. 2019;33(9):1170–1182. - PubMed
    1. Acheson D.T., Gresack J.E., Risbrough V.B. Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology. 2012;62(2):674–685. - PMC - PubMed
    1. Aguirre N., Barrionuevo M., Ramirez M.J., Del Rio J., Lasheras B. Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity. Neuroreport. 1999;10(17):3675–3680. - PubMed
    1. Alexander W. Pharmacotherapy for post-traumatic stress disorder in combat veterans: focus on antidepressants and atypical antipsychotic agents. P T. 2012;37(1):32–38. - PMC - PubMed
    1. Alshammari M.A., Khan M.R., Majid Mahmood H., Alshehri A.O., Alasmari F.F., Alqahtani F.M., Alasmari A.F., Alsharari S.D., Alhossan A., Ahmad S.F., Nadeem A., Alshammari T.K. Systemic TNF-alpha blockade attenuates anxiety and depressive-like behaviors in db/db mice through downregulation of inflammatory signaling in peripheral immune cells. Saudi Pharmaceut. J. 2020;28(5):621–629. - PMC - PubMed

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