Circulating endocannabinoids and affect regulation in human subjects
Introduction
Considerable data suggests that the endocannabinoid (EC) system influences a wide variety of neurobiological processes including affect and emotionality, the formation of memories, and the glucocorticoid-mediated stress response (Mechoulam and Parker, 2013). Thus, the EC system is an attractive area for research into the potential for pharmacotherapeutic targets for psychiatric illnesses (Rubino et al., 2015), particularly those involving disturbances of affect and emotion.
The EC system is composed of two eicosanoid ligands; anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two main receptors: CB1 and CB2. CB1 receptors are the most abundant G-protein coupled receptor in the nervous system and are concentrated throughout cortical, subcortical and cerebellar structures, though it should be noted that they are also present, in fewer numbers, in the periphery (Mechoulam and Parker, 2013). CB1 receptors are predominately found on GABAergic and glutamatergic neurons and exert a presynaptic inhibitory response when activated by EC molecules, or exogenous agonists like THC, the active ingredient in cannabis (Howlett et al., 2002). CB2 receptors are less numerous and were initially thought to be confined to the macrophagic immune cells, though current research supports a wider distribution in the CNS, particularly in microglial cells, and that they are involved in an immune-mediated neuroprotective role against inflammation (Ashton et al., 2006).
AEA and 2-AG are eicosanoid neuromodulatory lipids derived from membrane phospholipids. Both act presynaptically at EC receptors and are synthesized when and where they are required (Mechoulam and Parker, 2013) as opposed to being stored in vesicles. Considerable data within animal models documents the relationship between perturbations in the EC system and the constellation of symptoms present in depression and anxiety. Studies demonstrate a correlation between CB1 receptor-deficiency and depressive symptoms measured in mice such as anhedonia, anxiety, and heightened stress-response (Valverde and Torrens, 2012). In line with this relationship, chronic stress has been shown to compromise EC signaling in the brain (Hill et al., 2005; Wang et al., 2012) and augmentation of EC signaling can mitigate many of the adverse effects of chronic stress, such as anhedonia and anxiety (Bortolato et al., 2007; Rossi et al., 2010; Hill et al., 2013; Lomazzo et al., 2015). This suggests that impairments in EC signaling could relate to the development of stress-related psychiatric illnesses. Consistent with this, circulating levels of AEA and 2-AG have both been found to be reduced in disorders like major depression (Hill et al., 2008) or post-traumatic stress disorder (PTSD; Hill et al., 2013; Neumeister et al., 2013), or following exposure to chronic stress (Yi et al., 2016). However, there also reports of elevations in AEA and 2-AG levels in conditions such as minor depression (Hill et al., 2008) or chronic PTSD (Hauer et al., 2013), implying that dysregulation of EC signaling, regardless of directionality, may differentially contribute to the complex nature of psychiatric illnesses.
Despite evidence correlating EC levels and psychiatric conditions and the promise this research entails, few studies have been done in human subjects. During the development of CB1 receptor antagonists in humans for obesity treatment, it became apparent that blockade of the CB1 receptor did increase the incidence of anxiety and depression (Hill and Gorzalka, 2009; Christensen et al., 2007), supporting the preclinical data indicating that disruption of EC signaling did indeed regulate emotional states in humans. There are no published studies as of yet which detail the impact of pharmacological interventions targeted at AEA or 2-AG on emotional states in humans. Despite the lack of pharmacological studies, there is a series of studies which have shown that genetic variance in the enzyme FAAH in humans, which results in increased AEA signaling, is associated with reduced anxiety and fear, blunted amygdala activation to threat and enhanced cortical innervation of the amygdala (Hariri et al., 2009; Gee et al., 2016). To build off of the relatively limited number of human studies investigating alterations in EC in psychiatric illness, we compared serum AEA and 2-AG levels in a large group of individuals with and without DSM-5 psychiatric diagnoses as well as examine their affective intensity and lability in an attempt to correlate EC levels with psychopathology. Though we saw no significant differences within categorical DSM-5 defined disorders, we did find significant differences when examining dimensional measures of affect intensity and lability in study participants with and without a history of lifetime diagnosis of a psychiatric condition or personality disorder.
Section snippets
Subjects
One-hundred-seventy-five physically healthy subjects (mean age = 34.3 ± 8.2 years, 47.4% male) were recruited through public service announcements seeking out individuals who reported psychosocial difficulty related to one or more psychiatric disorders or who had little evidence of psychopathology. All subjects gave signed informed consent as approved by our Institutional Review Board (IRB). Subjects with bipolar disorder, schizophrenia, or mental retardation were excluded. Medical health was
Demographic/Behavioral characteristics of subjects (Table 2)
Healthy and psychiatric study participants differed significantly in age and displayed a trend for significance in distribution of ethnicity, but not in distribution of sex or in Hollingshead socioeconomic status (ses) score. Differences in age were due to a modest younger age among healthy vs. psychiatric study participants and to a smaller proportion of white study participants in the healthy, compared with psychiatric, study participants. While circulating EC levels did not correlate
Discussion
This is the first study to examine circulating ECs in a sizable group of study participants with and without history of psychiatric disorder in order to explore the relationship between circulating ECs and dimensions of affect and affect regulation. The primary finding in this study is that circulating ECs may have a modest, though statistically significant, inverse relationship with assessments of affect regulation (affective intensity and affective lability) even in the absence of
Role of funding source
The role of funding sources [National Institute of Mental Health: RO1 MH60836, RO1 MH63262, RO1 MH66984, RO1 MH80108 (Dr. Coccaro) and Canadian Institutes of Health Research (CIHR)] was to cover the cost of data collection and assays. Funding sources had no role in the design, analysis, or interpretation of the data.
Conflict of interest disclosures
Dr. Coccaro reports being on the Scientific Advisory Board of Azevan Pharmaceuticals and is a consultant to Avanir Pharmaceuticals, Inc.; Dr. Hill reports having received consulting fees from Pfizer International and receiving consulting fees and unrestricted operating funds from GW Pharmaceuticals; Dr. Lee reports being the recipient of a research grant from Azevan Pharmaceuticals, and from Avanir Pharmaceuticals; and Dr. Robinson reports no biomedical financial interests or potential
Acknowledgements
This work was supported in part by grants from the National Institute of Mental Health:
RO1 MH60836, RO1 MH63262, RO1 MH66984, RO1 MH80108 (Dr. Coccaro). MNH is a Tier II Canada Research Chair and is supported by operating funds from the Canadian Institutes of Health Research (CIHR). The authors would like to thank the Southern Alberta Mass Spectrometry Centre, located in and supported by the Cumming School of Medicine, University of Calgary, for their services in targeted liquid chromatography
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2020, Psychiatry ResearchCitation Excerpt :However, there are also reports of elevations in AEA and 2-AG blood levels in minor depression and chronic PTSD (Hill et al., 2008; Hauer et al., 2013). Possibly, abnormalities in endocannabinoid signaling, irrespective of direction, contribute to the pathophysiology of psychiatric disorders (Coccaro et al., 2018), including major depressive, post-traumatic, substance use disorders and schizophrenia that are associated with suicidality (Rihmer, 1996; Sher et al., 2001; Deutsch et al., 2008; Serafini et al., 2013; Elman et al., 2013; van Heeringen and Mann, 2014; Golf et al., 2016; Vieira et al., 2018). Endocannabinoid signaling is responsive to glucocorticoid hormones (Di et al., 2003), and the recruitment of endocannabinoid signaling by glucocorticoids mediates many of the physiological effects of glucocorticoid hormones, including negative feedback cessation of hypothalamic-pituitary-adrenal (HPA) axis activity (Evanson et al., 2010; Hill and McEwen, 2010; Hill et al., 2011).
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2019, Pharmacology Biochemistry and BehaviorCitation Excerpt :Additionally, EC signaling in the brain was compromised after chronic stress (Jennings et al. 2016; Morena et al. 2016), and augmenting EC signaling mitigated chronic stress-induced depressive-like behaviors (Griebel et al. 2018; Zhong et al. 2014). Furthermore, circulating levels of 2-AG were found to be reduced in patients with major depression (Coccaro et al. 2018). Consistent with this, we previously demonstrated that administering a low dose of MAGL inhibitors produced antidepressant effects in acute stress-exposed mice through long-term depression at glutamatergic synapses, whereas a high dose produced pro- and antidepressant effects in acute stress- and chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition in the hippocampus (Wang, Y. et al., 2017).
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2019, International Journal of Developmental NeuroscienceCitation Excerpt :In addition, in monozygotic twins discordant for schizophrenia, whole-body eCB level was lower in the diseased as compared to the unaffected twin, and a high level of eCBs was closely related to the reduction of schizophrenia symptoms (Koethe et al., 2018). Circulating plasma levels of eCBs are reduced in patients with mild depression and chronic post-traumatic stress syndrome (Green et al., 2013; Coccaro et al., 2018). Supplementation with eCBs has been shown to mitigate anxiety-like behavior associated with chronic stress; moreover, pharmacological CB1 receptor blockade and eCB in vivo transmission have demonstrated antidepressant effects (Hill and Gorzalka, 2005; Witkin et al., 2005).