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Translational investigation of the relationship between endocannabinoids, emotional memories, and PTSD

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Ney, LJ ORCID: 0000-0003-0209-8366 2021 , 'Translational investigation of the relationship between endocannabinoids, emotional memories, and PTSD', PhD thesis, University of Tasmania.

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Abstract

Background: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop following a traumatic experience. It is believed that PTSD is underpinned by multiple mechanisms, including maladaptive stress responding, negative emotional memories, and impaired fear extinction. Underneath each of these mechanisms are neurobiological abnormalities that could possibly be addressed pharmacologically. The endogenous cannabinoid (endocannabinoid) system is gaining increasing attention as such a biological target, with significant animal research showing that endocannabinoid signalling is critical to healthy stress responses, emotional memory consolidation, and fear extinction. However, studies that translate these animal findings to human subjects are lacking. The current thesis describes a research program intended to improve methods for studying endocannabinoid signalling in humans, as well as to determine whether endocannabinoid findings frequently reported in animal models of PTSD translate to humans. Doing so will provide better understanding of the potential for treating PTSD through the endocannabinoid system.
Method: The present thesis includes two narrative reviews and five empirical studies, which address: (1) quantitation of endocannabinoids in human saliva, hair, and plasma samples; (2) the effect of acute stress induction on salivary and plasma endocannabinoid levels; (3) the association between endocannabinoid genotypes and plasma levels on emotional memories; and (4) the association between endocannabinoid genotypes and plasma levels on fear extinction. The two studies describing methods for quantifying endocannabinoids are novel mass spectrometry methods and are fully validated as part of this thesis. The empirical studies examining stress responding, emotional memories, and fear extinction are cross-sectional and experimental studies that include PTSD, trauma-exposed, and non-trauma exposed participants. Participants underwent the Maastricht Acute Stress Task to induce stress induction in (3) while having saliva and plasma samples taken. In (4), participants had genetic and plasma samples taken while undergoing an emotional memory task. In (5), participants had skin conductance measured in a standard fear conditioning paradigm whilst having genetics and plasma samples taken.
Results: Endocannabinoids are quantifiable in hair, plasma, and saliva using simple mass spectrometry methods with high sensitivity. Endocannabinoids in saliva are stress responsive and are likely part of the autonomic rather than central nervous system. Genotypes associated with the cannabinoid receptor 1 were associated with higher intrusive memories of emotional imagery in PTSD subjects. Deliberately recalled negative images were remembered more poorly with higher endocannabinoid signalling, which translates animal findings accurately. Finally, better fear extinction was associated with genotypes associated with impaired endocannabinoid degradation enzymes, but only when the corresponding endocannabinoid plasma level was high. This finding also translates similar animal research to human subjects for the first time and implicates the important of the cannabinoid receptor 1 in extinction.
Conclusions: For the first time we have translated animal endocannabinoid research in PTSD mechanisms with high specificity to human participants. In particular, we find that both emotional memories and fear extinction are sensitive to cannabinoid receptor 1 signalling and are associated with circulating endocannabinoid levels. These findings have implications for how cannabinoid-based drugs should be developed and strongly suggest potential for efficacy in improving PTSD treatment outcomes. We also provide two novel mass spectrometry methods that can improve future endocannabinoid research in humans.

Item Type: Thesis - PhD
Authors/Creators:Ney, LJ
Keywords: endocannabinoids, posttraumatic stress disorder, emotional memories, fear extinction, genetics
Copyright Information:

Copyright 2021 the author

Additional Information:

Chapter 2 appears to be, in part, the equivalent of a pre-print version of an article published as: Ney, L. J., Matthews, A., Bruno, R., Felmingham, K. L., 2018. Modulation of the endocannabinoid system by sex hormones: Implications for posttraumatic stress disorder, Neuroscience and biobehavioral reviews, 94, 302-320. A post print equivalent is located at chapter 10 (appendix A).

Chapter 3 appears to be the equivalent of a post-print version of an article published as: Ney, L. J., Felmingham, K. L., Bruno, R., Matthews, A., Nichols, D. S., 2020. Simultaneous quantification of endocannabinoids, oleoylethanolamide and steroid hormones in human plasma and saliva, Journal of chromatography B, 1152, 122252.

Chapter 4 appears to be the equivalent of a post-print version of an article published as: Ney, L. J., Felmingham, K. L., Bruno, R., Matthews, A., Nichols, D. S., 2021. Chloroform-based liquid-liquid extraction and LC-MS/MS quantification of endocannabinoids, cortisol and progesterone in human hair, Journal of pharmaceutical and biomedical analysis, 201, 114103.

Chapter 5 appears to be the equivalent of a pre-print version of an article published as: Ney, L. J., Stone, C., Nichols, D., Felmingham, K., Bruno, R., Matthews, A., 2021. Endocannabinoid reactivity to acute stress: Investigation of the relationship between salivary and plasma levels, Biological psychology, 159, 108022.

Chapter 7 appears to be the equivalent of the peer reviewed version of the following article: Ney, L. J., Matthews, A., Hsu, C. K., Zuj, D. V., Nicholson, E., Steward, T., Nichols, D., Graham, B., Harrison, B., Bruno, R., Felmingham, K., 2021. Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning, Depression & anxiety, 38(10), 1087–1099, which has been published in final form at https://doi.org/10.1002/da.23170. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

Chapter 8 appears to be the equivalent of a post-print version of an article published as: Ney, L. J., Matthews, A., Bruno, R., Felmingham, K. L., 2018. Cannabinoid interventions for PTSD : Where to next?, Progress in neuro-psychopharmacology and biological psychiatry, 93, 124-140.

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