Publications by authors named "Cecilia J Hillard"

162 Publications

Contribution of the Adenosine 2A Receptor to Behavioral Effects of Tetrahydrocannabinol, Cannabidiol and PECS-101.

Molecules 2021 Sep 2;26(17). Epub 2021 Sep 2.

Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

The cannabis-derived molecules, ∆ tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. In addition to their other pharmacological targets, both THC and CBD are competitive inhibitors of the equilibrative nucleoside transporter-1 (ENT-1), a primary inactivation mechanism for adenosine, and thereby increase adenosine signaling. The goal of this study was to examine the role of adenosine A2A receptor activation in the effects of intraperitoneally administered THC alone and in combination with CBD or PECS-101, a 4'-fluorinated derivative of CBD, in the cannabinoid tetrad, elevated plus maze (EPM) and marble bury assays. Comparisons between wild-type (WT) and A2AR knock out (A2AR-KO) mice were made. The cataleptic effects of THC were diminished in A2AR-KO; no other THC behaviors were affected by A2AR deletion. CBD (5 mg/kg) potentiated the cataleptic response to THC (5 mg/kg) in WT but not A2AR-KO. Neither CBD nor THC alone affected EPM behavior; their combination produced a significant increase in open/closed arm time in WT but not A2AR-KO. Both THC and CBD reduced the number of marbles buried in A2AR-KO but not WT mice. Like CBD, PECS-101 potentiated the cataleptic response to THC in WT but not A2AR-KO mice. PECS-101 also reduced exploratory behavior in the EPM in both genotypes. These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling.
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http://dx.doi.org/10.3390/molecules26175354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434367PMC
September 2021

Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial.

Psychoneuroendocrinology 2021 Jul 9;132:105355. Epub 2021 Jul 9.

University of Texas at Austin, Department of Psychiatry and Behavioral Sciences, 1601 Trinity St, Bldg B, Austin, TX 78712, United States.

Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall.

Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect.

Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: -0.623 to -0.005; BDNF 95% CI: -0.941 to -0.005).

Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105355DOI Listing
July 2021

Dynamic Change of Endocannabinoid Signaling in the Medial Prefrontal Cortex Controls the Development of Depression After Neuropathic Pain.

J Neurosci 2021 Sep 9;41(35):7492-7508. Epub 2021 Jul 9.

Departments of Anesthesiology

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c- and electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression. Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.
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http://dx.doi.org/10.1523/JNEUROSCI.3135-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412994PMC
September 2021

Aerobic exercise reduces anxiety and fear ratings to threat and increases circulating endocannabinoids in women with and without PTSD.

Ment Health Phys Act 2021 Mar 2;20. Epub 2020 Nov 2.

Department of Kinesiology at the University of Wisconsin-Madison, Madison, WI - USA.

Reductions in state anxiety have been reported following an acute bout of aerobic exercise. However, less is known regarding anxiety and fear ratings to specific threatening stimuli following an acute bout of aerobic exercise in women with PTSD. Moreover, the mechanisms responsible for the anxiolytic effects of exercise are not fully understood, although recent studies suggest a role for the endocannabinoid (eCB) system. Thus, this study utilized a randomized, counterbalanced approach to examine anxiety and fear ratings to predictable or unpredictable electric shock administration and circulating concentrations of eCBs and mood states immediately following moderate-intensity aerobic exercise (30 min on treadmill at 70-75% maximum heart rate) and a quiet rest control condition in women with and without a history of trauma, and in women with PTSD (N=42). Results revealed that anxiety and fear ratings to unpredictable and predictable threats were significantly (<.05) lower following exercise compared to quiet rest, with correlational analyses indicating those with greater increases in circulating eCBs had greater reductions in anxiety and fear ratings to unpredictable and predictable threats following exercise. Also, there were significant (<.05) reductions in fatigue, confusion, total mood disturbance, and increases in positive affect following exercise for the entire sample. Non-trauma controls and PTSD groups reported significant (<.05) increases in vigor, with additional mood improvements following exercise for the PTSD group (i.e., decreases in state anxiety, negative affect, tension, anger, and depression). Results from this study suggest that aerobic exercise exerts psychological benefits in women with PTSD, potentially due to exercise-induced increases in circulating concentrations of eCBs.
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http://dx.doi.org/10.1016/j.mhpa.2020.100366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208522PMC
March 2021

Inactivation of the CB receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis.

Brain Pathol 2021 May 13:e12972. Epub 2021 May 13.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain.

The activation of the cannabinoid receptor type-2 (CB ) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB receptor knock-out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP-43 transgenic mice expressing the CB receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP-43 transgenic mice expressing the CB receptor. Evidence of glial reactivity, measured using GFAP and Iba-1 immunostaining, was seen in double mutants at 65 days, but not in TDP-43 transgenic mice expressing the CB receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP-43 transgenic mice expressing the CB receptor. We also investigated the consequences of a pharmacological inactivation of the CB receptor using the selective antagonist AM630 in TDP-43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.
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http://dx.doi.org/10.1111/bpa.12972DOI Listing
May 2021

Circulating endocannabinoids and prospective risk for depression in trauma-injury survivors.

Neurobiol Stress 2021 May 4;14:100304. Epub 2021 Feb 4.

Medical College of Wisconsin, Department of Surgery, Division of Trauma & Acute Care Surgery, Milwaukee, WI, USA.

Biological mechanisms associated with response to trauma may impact risk for depression. One such mechanism is endocannabinoid signaling (eCB), a neuromodulatory system comprised of the CB1 subtype of cannabinoid receptors (CB1R), encoded by the gene, and two primary endogenous ligands: 2-arachidonoylglycerol (2-AG) and -arachidonylethanolamine (AEA), hydrolyzed by monoacylglycerol lipase (gene name and fatty acid amide hydrolase (gene name . Preclinical data suggest that eCB/CB1R signaling acts as a stress buffer and its loss or suppression increases depression-like behaviors. We examined circulating concentrations of the eCBs (2-AG and AEA) days and six months after a traumatic injury as a marker of eCB/CB1R signaling and as predictors of Center for Epidemiologic Studies of Depression Scale-Revised [CESD-R] scores as a measure of depression severity six months after injury. We also explored associations of and genetic variance with depression severity at six months. Results from hierarchical multiple linear regressions showed that higher 2-AG serum concentrations after trauma predicted greater depression at six months ( = 0.23,  = 0.007); neither AEA after trauma, nor 2-AG and AEA at six months were significant predictors ('s > 0.305). Carriers of minor allele for the putative single nucleotide polymorphism in the gene rs806371 (β = 0.19,  = 0.024) experienced greater depression at six months. These data suggest that the eCB signaling system is highly activated following trauma and that eCB/CB1R activity contributes to long-term depression risk.
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http://dx.doi.org/10.1016/j.ynstr.2021.100304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876629PMC
May 2021

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill.

Transl Psychiatry 2021 01 18;11(1):58. Epub 2021 Jan 18.

Section of BMT & Cellular Therapies; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II-IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more-not less-depressive symptoms.
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http://dx.doi.org/10.1038/s41398-020-01164-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812704PMC
January 2021

Inhibition of Fatty Acid Amide Hydrolase (FAAH) During Adolescence and Exposure to Early Life Stress may Exacerbate Depression-like Behaviors in Male and Female Rats.

Neuroscience 2021 02 25;455:89-106. Epub 2020 Dec 25.

School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa 3498838, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa 3498838, Israel. Electronic address:

Early-life stress (ELS) is associated with later onset of depression. Early cannabis use may be a risk factor that interacts with environmental factors to increase the risk of psychopathologies. We aimed to examine the long-term effects of ELS on depression- and anxiety-like behavior, and examine whether chronic fatty acid amide hydrolase (FAAH) inhibition during mid-adolescence could ameliorate or exacerbate ELS effects on behavior. Male and female rats were exposed to ELS during post-natal days (P) 7-14, injected with the FAAH inhibitor URB597 (0.4 mg/kg, i.p.) or vehicle for 2 weeks during mid-adolescence (P30-45) or late-adolescence (P45-60). Rats were tested in adulthood for behavior and alterations in CB1 receptors (CB1r) and glucocorticoid receptors (GRs) in the brains' stress circuit. ELS produced decreased social preference, impaired social recognition, increased learned helplessness and anxiety-like behavior. Administering URB597 during mid-adolescence did not prevent the deleterious long-term effects of ELS on behavior in males and females. When URB597 was administered during late-adolescence, it ameliorated ELS-induced depression- and anxiety-like behavior. Moreover, in males, ELS and URB597 decreased CB1r levels in the prefrontal cortex (PFC) and CA1 and GRs in the PFC and basolateral amygdala (BLA). In females, ELS and URB decreased CB1r in the BLA and GRs in the CA1 and BLA. The findings suggest that mid-adolescence, as opposed to late-adolescence, may not be a potential developmental period for chronic treatment with FAAH inhibitors and that sex-dependent alterations in CB1r and GRs expression in the BLA-PFC-CA1 circuit may contribute to the depressive behavioral phenotype.
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http://dx.doi.org/10.1016/j.neuroscience.2020.12.022DOI Listing
February 2021

Peripherally restricted cannabinoid type 1 receptor (CB1R) antagonist, AM6545, potentiates stress-induced hypothalamic-pituitary-adrenal axis activation via a non-CB1R mechanism.

Endocrine 2021 04 20;72(1):297-300. Epub 2020 Nov 20.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

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http://dx.doi.org/10.1007/s12020-020-02549-1DOI Listing
April 2021

Endocannabinoids and related lipids in serum from patients with amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 3;63(1):120-126. Epub 2020 Nov 3.

Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.

Background: The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity.

Methods: Serum concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2-oleoylglycerol (2-OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity.

Results: Binary logistic regression revealed that, after controlling for age and gender, 2-AG, 2-OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity.

Conclusions: These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.
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http://dx.doi.org/10.1002/mus.27096DOI Listing
January 2021

Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior.

Mol Psychiatry 2020 Oct 22. Epub 2020 Oct 22.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

Enhancing endocannabinoid signaling produces anxiolytic- and antidepressant-like effects, but the neural circuits involved remain poorly understood. The medial habenula (MHb) is a phylogenetically-conserved epithalamic structure that is a powerful modulator of anxiety- and depressive-like behavior. Here, we show that a robust endocannabinoid signaling system modulates synaptic transmission between the MHb and its sole identified GABA input, the medial septum and nucleus of the diagonal band (MSDB). With RNAscope in situ hybridization, we demonstrate that key enzymes that synthesize or degrade the endocannabinoids 2-arachidonylglycerol (2-AG) or anandamide are expressed in the MHb and MSDB, and that cannabinoid receptor 1 (CB1) is expressed in the MSDB. Electrophysiological recordings in MHb neurons revealed that endogenously-released 2-AG retrogradely depresses GABA input from the MSDB. This endocannabinoid-mediated depolarization-induced suppression of inhibition (DSI) was limited by monoacylglycerol lipase (MAGL) but not by fatty acid amide hydrolase. Anatomic and optogenetic circuit mapping indicated that MSDB GABA neurons monosynaptically project to cholinergic neurons of the ventral MHb. To test the behavioral significance of this MSDB-MHb endocannabinoid signaling, we induced MSDB-specific knockout of CB1 or MAGL via injection of virally-delivered Cre recombinase into the MSDB of Cnr1 or Mgll mice. Relative to control mice, MSDB-specific knockout of CB1 or MAGL bidirectionally modulated 2-AG signaling in the ventral MHb and led to opposing effects on anxiety- and depressive-like behavior. Thus, depression of synaptic GABA release in the MSDB-ventral MHb pathway may represent a potential mechanism whereby endocannabinoids exert anxiolytic and antidepressant-like effects.
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http://dx.doi.org/10.1038/s41380-020-00905-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060365PMC
October 2020

Signaling through the type 2 cannabinoid receptor regulates the severity of acute and chronic graft-versus-host disease.

Blood 2021 03;137(9):1241-1255

Department of Microbiology.

Graft-versus-host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R), which is expressed on nearly all immune cells, and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells or administration of a selective CB2R pharmacological antagonist exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells, indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T-cell alloreactivity. Using a novel CB2ReGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists Δ9-tetrahydrocannabinol (THC) and JWH-133 revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contributed to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and extracellular regulated kinase phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. This study shows that the CB2R plays a critical role in the regulation of GVHD and suggests that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.
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http://dx.doi.org/10.1182/blood.2020004871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933769PMC
March 2021

Development of High-Specificity Fluorescent Probes to Enable Cannabinoid Type 2 Receptor Studies in Living Cells.

J Am Chem Soc 2020 10 29;142(40):16953-16964. Epub 2020 Sep 29.

Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223, Madrid, Spain.

Pharmacological modulation of cannabinoid type 2 receptor (CBR) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CBR signaling, especially in cell-type and tissue-dependent contexts. Herein, we report for the first time a versatile ligand platform for the modular design of a collection of highly specific CBR fluorescent probes, used successfully across applications, species, and cell types. These include flow cytometry of endogenously expressing cells, real-time confocal microscopy of mouse splenocytes and human macrophages, as well as FRET-based kinetic and equilibrium binding assays. High CBR specificity was demonstrated by competition experiments in living cells expressing CBR at native levels. The probes were effectively applied to FACS analysis of microglial cells derived from a mouse model relevant to Alzheimer's disease.
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http://dx.doi.org/10.1021/jacs.0c05587DOI Listing
October 2020

Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to early life stress.

Eur Neuropsychopharmacol 2020 10 2;39:70-86. Epub 2020 Sep 2.

School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa 3498838, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, 3498838, Israel. Electronic address:

Early life stress (ELS) may increase predisposition to depression. Despite extensive research, there is still a lack of knowledge of how to optimally treat depression. We aimed to establish a role for the endocannabinoid (ECB) system within the hippocampal-nucleus accumbens (NAc) network as a possible effective target in combating the pathophysiological development of depression-like behavior and neuronal alterations that are precipitated by ELS. Male and female rats were exposed to ELS during post-natal days (P) 7-14, injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184 for 2 weeks during late-adolescence (P45-60). Rats were tested starting at P90 for depressive- and anxiety-like behaviors as well as social preference and recognition; alterations in FAAH and MAGL activity; the expression of brain-derived neurotrophic factor (BDNF); and plasticity in the hippocampal-NAc pathway. FAAH and MAGL inhibitors during late-adolescence prevented: (i) the long-term effects of ELS on depression- and anxiety-like behavior and the impairment in social behavior and neuronal plasticity in males and females; (ii) ELS-induced alterations in MAGL activity in males' hippocampus and females' hippocampus and NAc; and (iii) ELS-induced alterations in BDNF in males' hippocampus and NAc and females' hippocampus. Significant correlations were observed between alterations in MAGL and BDNF levels and the behavioral phenotype. The findings suggest that alterations in MAGL activity and BDNF expression in the hippocampal-NAc network contribute to the depressive-like behavioral phenotype in ELS males and females. Moreover, the study suggests FAAH and MAGL inhibitors as potential intervention drugs for depression.
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http://dx.doi.org/10.1016/j.euroneuro.2020.08.005DOI Listing
October 2020

Meet Your Stress Management Professionals: The Endocannabinoids.

Trends Mol Med 2020 10 28;26(10):953-968. Epub 2020 Aug 28.

Neuroscience Research Center, USA; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address:

The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain. Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure. Chronic stress exposure increases vulnerability to mental illness, so the ECSS has attracted attention as a potential therapeutic target for the prevention and treatment of stress-related psychopathology. We discuss human genetic studies indicating that the ECSS contributes to risk for mental illness in those exposed to severe stress and trauma early in life, and we explore the potential difficulties in pharmacological manipulation of the ECSS.
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http://dx.doi.org/10.1016/j.molmed.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530069PMC
October 2020

Traumatic Brain Injury and Alcohol Drinking Alter Basolateral Amygdala Endocannabinoids in Female Rats.

J Neurotrauma 2021 02 30;38(4):422-434. Epub 2020 Sep 30.

Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.

Traumatic brain injury (TBI) affects approximately 3 million Americans yearly and increases vulnerability to developing psychiatric comorbidities. Alcohol use disorder (AUD) is the most prevalent psychiatric diagnosis preceding injury and TBI may increase subsequent alcohol use. The basolateral amygdala (BLA) is a limbic structure commonly affected by TBI that is implicated in anxiety and AUD. Endocannabinoids (eCBs) regulate synaptic activity in the BLA, and BLA eCB modulation alters anxiety-like behavior and stress reactivity. Previous work from our laboratories showed that systemic eCB degradation inhibition ameliorates TBI-induced increases in anxiety-like behavior and motivation to respond for alcohol in male rats. Here, we used a lateral fluid percussion model to test moderate TBI effects on anxiety-like behavior, alcohol drinking, and eCB levels and cell signaling in BLA, as well as the effect of alcohol drinking on anxiety-like behavior and the BLA eCB system, in female rats. Our results show that TBI does not promote escalation of operant alcohol self-administration or increase anxiety-like behavior in female rats. In the BLA, TBI and alcohol drinking alter tissue amounts of 2-arachidonoylglycerol (2-AG) and -arachidonoylethanolamine (anandamide; AEA) 1 h post-injury, and 2-AG levels remain low 11 days post-injury. Eleven days after injury, BLA pyramidal neurons were hyperexcitable, but measures of synaptic transmission and eCB signaling were unchanged. These data show that TBI impacts BLA 2-AG tissue levels, that this effect is modified by alcohol drinking, and also that TBI increases BLA cell excitability.
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http://dx.doi.org/10.1089/neu.2020.7175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875607PMC
February 2021

Circulating endocannabinoid concentrations in grieving adults.

Psychoneuroendocrinology 2020 10 10;120:104801. Epub 2020 Jul 10.

Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin, 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin, 53226, USA; Institute for Health and Equity, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, Wisconsin, 53226, USA. Electronic address:

Bereavement is one of the most intense, distressing, and traumatic events an elderly person will experience. The symptom responses to bereavement vary, particularly during the first year. However, the neurobiology underlying the symptom variance in grief is poorly understood. The endocannabinoid signaling (ECS) system is stress-responsive; mounting evidence implicates the central ECS in psychopathology. The current study aimed to investigate the hypothesis that the ECS is abnormal in grief, using circulating eCB concentrations as a biomarker of central ECS. A predominantly older sample of grief participants, within 13 months following the death of a loved one, and healthy comparison (HC) participants were studied. Associations of circulating eCBs with symptom variance in grievers were also examined. A total of 61 (grief: n = 44; HC: n = 17) adults completed cross-sectional clinical assessments and a fasting blood draw. Assessments included the Inventory of Complicated Grief scale; the 17-item Hamilton Depression Rating Scale; and the Hamilton Anxiety scale. Serum eCB concentrations (i.e., N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) were quantified using isotope dilution, liquid chromatography-mass spectrometry. Relative to HC participants, grievers had significantly elevated serum AEA but similar 2-AG concentrations. In grievers, serum AEA concentrations were positively associated with depressive and anxiety symptoms, but only in those with low grief symptoms. These novel findings indicate that elevated circulating eCB concentrations are found following bereavement. The eCB signaling response varies based on the degree of grief severity. Circulating eCB measures may have the potential to serve as biomarkers of prolonged grief disorder.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348598PMC
October 2020

Hot-Water Bathing Improves Symptoms in Patients with Cyclic Vomiting Syndrome and Is Modulated by Chronic Cannabis Use.

Dig Dis Sci 2021 04 29;66(4):1153-1161. Epub 2020 May 29.

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Background: Cyclic vomiting syndrome (CVS) is a chronic functional GI disorder; a characteristic compulsive "hot-water bathing" pattern is reported to alleviate symptoms during an acute episode. There is limited data on this bathing pattern: proposed mechanisms include core temperature increase via effects on cannabinoid type 1 receptors in the brain, skin transient receptor potential vanilloid 1 receptor stimulation, and blood flow shift from viscera to skin.

Aims: We thus sought to characterize the hot-water bathing pattern in patients with CVS and identify differences between heavy cannabis users in comparison to occasional and non-users.

Methods: We conducted a cross-sectional study of 111 patients with CVS at a single tertiary referral center. Questionnaires regarding clinical characteristics, hot-water bathing, and cannabis use were administered. Patients were classified based on cannabis usage into regular cannabis users (≥ 4 times/week), and occasional + non-users (< 4 times/week and no current use).

Results: A total of 81 (73%) respondents reported the hot-water bathing behavior during an episode. The majority (> 80%) noted a marked improvement in nausea, vomiting, abdominal pain and symptoms associated with panic. Regular cannabis users were more likely to use "very-hot" water (50% vs. 16%, p = 0.01) and time to relief of symptoms was longer (> 10 min) in this group, compared to the rest of the cohort.

Conclusions: Hot-water bathing relieves both GI and symptoms related to panic in most patients which appear to be modulated by chronic cannabis use. These findings can help inform future physiologic studies in CVS pathogenesis.
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http://dx.doi.org/10.1007/s10620-020-06343-xDOI Listing
April 2021

Adverse maternal environment and western diet impairs cognitive function and alters hippocampal glucocorticoid receptor promoter methylation in male mice.

Physiol Rep 2020 04;8(8):e14407

Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Adverse maternal environment (AME) and high-fat diet in early childhood increase the risk of cognitive impairment and depression later in life. Cognitive impairment associates with hippocampal dysfunction. A key regulator of hippocampal function is the glucocorticoid receptor. Increased hippocampal GR expression associates with cognitive impairment and depression. Transcriptional control of GR relies in part upon the DNA methylation status at multiple alternative initiation sites that are tissue specific, with exon 1.7 being hippocampal specific. Increased exon 1.7 expression associates with upregulated hippocampal GR expression in early life stress animal models. However, the effects of AME combined with postweaning western diet (WD) on offspring behaviors and the expression of GR exon 1 variants in the hippocampus are unknown. We hypothesized that AME and postweaning WD would impair cognitive function and cause depression-like behavior in offspring in conjunction with dysregulated hippocampal expression of total GR and exon 1.7 variant in mice. We found that AME-WD impaired learning and memory in male adult offspring concurrently with increased hippocampal expression of total GR and GR 1.7. We also found that increased GR 1.7 expression was associated with decreased DNA methylation at the GR 1.7 promoter. We speculate that decreased DNA methylation at the GR 1.7 promoter plays a role in AME-WD induced increase of GR in the hippocampus. This increased GR expression may subsequently contribute to hippocampus dysfunction and lead to the cognitive impairment seen in this model.
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http://dx.doi.org/10.14814/phy2.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183239PMC
April 2020

Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

Neuropsychopharmacology 2020 11 17;45(12):1974-1985. Epub 2020 Apr 17.

Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.

Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite comparable self-administration and extinction, females displayed a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock, tested across a range of intensities, failed to potentiate cocaine-primed reinstatement in females. However, restraint potentiated reinstatement in both sexes. While sex differences in stressor-induced plasma corticosterone (CORT) elevations and defensive behaviors were not observed, differences were evident in footshock-elicited ultrasonic vocalizations. CORT administration, at a dose which recapitulates stressor-induced plasma levels, reproduced stress-potentiated cocaine-primed reinstatement in both sexes. In females, CORT effects varied across the estrous cycle; CORT-potentiated reinstatement was only observed during diestrus and proestrus. As in males, CORT-potentiated cocaine seeking in females was localized to the PrL-PFC and both CORT- and restraint-potentiated cocaine seeking required PrL-PFC CB1R activation. In addition, ex vivo whole-cell electrophysiological recordings from female layer V PrL-PFC pyramidal neurons revealed CB1R-dependent CORT-induced suppression of inhibitory synaptic activity, as previously observed in males. These findings demonstrate that, while stress potentiates cocaine seeking via PrL-PFC CB1R in both sexes, sensitivity to cocaine priming injections is greater in females, CORT-potentiating effects vary with the estrous cycle, and whether reactivity to specific stressors may manifest as drug seeking depends on biological sex.
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http://dx.doi.org/10.1038/s41386-020-0674-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547655PMC
November 2020

Circadian Misalignment of the 24-hour Profile of Endocannabinoid 2-Arachidonoylglycerol (2-AG) in Obese Adults.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois.

Context: The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day.

Objective: We sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant.

Design: With fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900.

Participants: Twelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied.

Results: We observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants.

Conclusions: Obesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.
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http://dx.doi.org/10.1210/clinem/dgaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015463PMC
March 2020

Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.

Proc Natl Acad Sci U S A 2020 01 16;117(1):650-655. Epub 2019 Dec 16.

Department of Neurobiology, National Centre for Biological Sciences, 560065 Bangalore, India;

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CBR), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced -arachidonoylethanolamine (AEA), an endogenous ligand of CBR. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.
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http://dx.doi.org/10.1073/pnas.1910322116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955336PMC
January 2020

Psychological and endocannabinoid responses to aerobic exercise in substance use disorder patients.

Subst Abus 2019 Nov 15:1-12. Epub 2019 Nov 15.

Department of Kinesiology, University of Wisconsin, Madison, Wisconsin, USA.

: Exercise has been examined as an adjunctive treatment for substance use disorders (SUDs), yet few exercise interventions have been conducted among patients undergoing intensive outpatient (IOP) treatment, who may be the most vulnerable to relapse and for whom exercise could provide the most benefits. This study examined the effects of aerobic exercise, in addition to IOP treatment, on psychological variables and endocannabinoids in individuals with SUDs. : Twenty-one SUD patients (mean age 35 years) were recruited from local IOPs. Participants were randomized to either treatment-as-usual (TAU, at their outpatient clinic) or TAU plus aerobic exercise training (EX). EX participants engaged in supervised, moderate-intensity exercise for 30 min, 3 times/week for 6 weeks. TAU participants came into the laboratory once per week for assessments and a 30-min quiet rest session. Participants provided blood samples and completed questionnaires evaluating substance use, mood states, depression, anxiety, perceived stress, self-efficacy to abstain from substance use, and craving. Data were analyzed with Mann-Whitney tests or mixed model ANOVAs to determine group differences in outcomes acutely and over 6 weeks. : Over 6 weeks, there were reductions in perceived stress ( < 0.01) and craving ( < 0.05) for both groups. There were no group differences in abstinence rates or changes from baseline in self-efficacy, depression, or anxiety ( > 0.05). Acutely, both exercise and quiet rest sessions led to reductions in craving, tension, depression, anger, confusion, and total mood disturbance (all s < 0.05). In addition, the EX group experienced acute increases in vigor and circulating concentrations of the endocannabinoid, anandamide ( < 0.01). : An adjunctive aerobic exercise program during SUD treatment was associated with similar reductions in perceived stress and drug craving as standard care. Thirty minutes of exercise or quiet rest led to acute improvements in mood, but exercise produced the additional benefit of increases in vigor and circulating anandamide.
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http://dx.doi.org/10.1080/08897077.2019.1680480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225058PMC
November 2019

Patterns of Cannabis Use in Patients With Cyclic Vomiting Syndrome.

Clin Gastroenterol Hepatol 2020 05 25;18(5):1082-1090.e2. Epub 2019 Jul 25.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.

Background & Aims: Some patients with cyclic vomiting syndrome (CVS) use cannabis to relieve stress and for its antiemetic properties. However, chronic cannabis use has been associated paradoxically with cannabinoid hyperemesis syndrome (CHS) and some patients with CVS are thought to have CHS. We sought to characterize patterns of cannabis use by patients with CVS and identify those who could be reclassified as having CHS.

Methods: We performed a cross-sectional study of 140 patients with CVS (72% female; mean age, 37 ± 13 y) seen at a specialized clinic. Patients were screened for cannabis use with the cannabis use disorder identification test. Patients were classified as regular (use ≥4 times/wk) or occasional users (<4 times/wk).

Results: Forty-one percent of patients were current cannabis users, with 21% reporting regular use. Regular users were more likely to be male and to report an anxiety diagnosis, and smoked cannabis with higher tetrahydrocannabinol content and for a longer duration. Most users reported that cannabis helped control CVS symptoms. Among all cannabis users, 50 of 57 (88%) reported that they had abstained for longer than 1 month, but only 1 user reported resolution of CVS episodes during the abstinence period. This patient subsequently resumed using cannabis but remains free of symptoms.

Conclusions: Cannabis is used commonly among patients with CVS-patients report relief of symptoms with use. We found 21% of patients with CVS to be regular users, but only 1 met the Rome IV criteria for CHS. Longitudinal studies are needed to determine the relationships among cannabis use, hyperemesis, and mood symptoms.
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http://dx.doi.org/10.1016/j.cgh.2019.07.039DOI Listing
May 2020

Loss of exercise- and stress-induced increases in circulating 2-arachidonoylglycerol concentrations in adults with chronic PTSD.

Biol Psychol 2019 07 9;145:1-7. Epub 2019 Apr 9.

Department of Kinesiology, University of Wisconsin-Madison, 2000 Observatory Dr., Madison, WI, 53706, USA.

The endocannabinoid (eCB) system is a modulatory system that is both altered by stress and mediates the effects of acute stress, including contributing to restoration of homeostasis. Earlier studies suggest that circulating eCBs are dysregulated in adults with post-traumatic stress disorder (PTSD); however, it is not known whether circulating eCBs remain responsive to stress. The purpose of this study was to examine eCB and psychological responses to physical (exercise) and psychosocial (Trier Social Stress Test) stressors, using a randomized, counterbalanced procedure in adults with PTSD and healthy controls (N = 20, mean age = 24, SD = 7 yrs). Results from mixed-design, repeated measures ANOVAs revealed significant increases (p <  .05) in N-arachidonoylethanolamine (AEA) and oleoylethanolamide (OEA) following exercise and psychosocial stress in both groups. However, only the control group exhibited a significant increase (p < .05) in 2-arachidonoylglycerol (2-AG) following exercise and psychosocial stress exposure. These data extend our current understanding of circulating eCB responsiveness in PTSD, and provide preliminary evidence to suggest that the eCB system is hypoactive in PTSD following exposure to physical and psychosocial stressors.
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http://dx.doi.org/10.1016/j.biopsycho.2019.04.002DOI Listing
July 2019

Serum Endocannabinoid and Mood Changes after Exercise in Major Depressive Disorder.

Med Sci Sports Exerc 2019 09;51(9):1909-1917

Department of Kinesiology, University of Wisconsin-Madison, Madison WI.

The endocannabinoid (eCB) system is implicated in the pathophysiology of depression and is responsive to acute exercise in healthy adults.

Purpose: We aimed to describe acute changes in serum eCB across a prescribed moderate (MOD) and a self-selected/preferred (PREF) intensity exercise session in women with major depressive disorder (MDD) and determine relationships between changes in eCB and mood states.

Methods: Women with MDD (n = 17) exercised in separate sessions for 20 min on a cycle ergometer at both MOD or PREF in a within-subjects design. Blood was drawn before and within 10 min after exercise. Serum concentrations of eCB (anandamide [AEA], 2-arachidonoylglycerol) and related lipids (palmitoylethanolamine, oleoylethanolamine, 2-oleoylglycerol) were quantified using stable isotope-dilution, liquid chromatography/mass spectrometry/mass spectrometry. The profile of mood states and state-trait anxiety inventory (state only) were completed before, 10 min and 30 min postexercise.

Results: Significant elevations in AEA (P = 0.013) and oleoylethanolamine (P = 0.024) occurred for MOD (moderate effect sizes: Cohen's d = 0.58 and 0.41, respectively). Significant (P < 0.05) moderate negative associations existed between changes in AEA and mood states for MOD at 10 min (depression, confusion, fatigue, total mood disturbance [TMD] and state anxiety) and 30 min postexercise (confusion, TMD and state anxiety). Significant (P < 0.05) moderate negative associations existed between 2-arachidonoylglycerol and mood states at 10 min (depression and confusion) and 30 min postexercise (confusion and TMD). Changes in eCB or related lipids or eCB-mood relationships were not found for PREF.

Conclusion: Given the broad, moderate-strength relationships between improvements in mood states and eCB increases after MOD, it is plausible that the eCB system contributes to the mood-enhancing effects of prescribed acute exercise in MDD. Alternative mechanisms are likely involved in the positive mood state effects of preferred exercise.
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http://dx.doi.org/10.1249/MSS.0000000000002006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727944PMC
September 2019

Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.

Exp Eye Res 2019 05 21;182:74-84. Epub 2019 Mar 21.

The Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA. Electronic address:

CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R receptors in mouse and the consequences of their activation on cellular signaling, migration and proliferation in cultured bovine corneal epithelial cells (CECs). Using a novel mouse model, we provide evidence that corneal injury increases CB2R receptor expression in cornea. The CB2R agonist JWH133 induces chemorepulsion in cultured bovine CECs but does not alter CEC proliferation. The signaling profile of CB2R activation is activating MAPK and increasing cAMP accumulation, the latter perhaps due to G-coupling. Lipidomic analysis in bovine cornea shows a rise in acylethanolamines including the endocannabinoid anandamide 1 h after injury. In vivo, CB2R deletion and pharmacological block result in a delayed course of wound closure. In summary, we find evidence that CB2R receptor promoter activity is increased by corneal injury and that these receptors are required for the normal course of wound closure, possibly via chemorepulsion.
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http://dx.doi.org/10.1016/j.exer.2019.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504573PMC
May 2019

Early life stress alters the developmental trajectory of corticolimbic endocannabinoid signaling in male rats.

Neuropharmacology 2019 03 26;146:154-162. Epub 2018 Nov 26.

Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA. Electronic address:

Early-life stress modulates the development of cortico-limbic circuits and increases vulnerability to adult psychopathology. Given the important stress-buffering role of endocannabinoid (eCB) signaling, we performed a comprehensive investigation of the developmental trajectory of the eCB system and the impact of exposure to early life stress induced by repeated maternal separation (MS; 3 h/day) from postnatal day 2 (PND2) to PND12. Tissue levels of the eCB molecules anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured after MS exposures, as well under basal conditions at juvenile (PND14), adolescent (PND40) and adult (PND70) timepoints in the prefrontal cortex (PFC), amygdala and hippocampus. We also examined the effects of MS on CB receptor binding in these three brain regions at PND40 and PND70. AEA content was found to increase from PND2 into adulthood in a linear manner across all brain regions, while 2-AG was found to exhibit a transient spike during the juvenile period (PND12-14) within the amygdala and PFC, but increased in a linear manner across development in the hippocampus. Exposure to MS resulted in bidirectional changes in AEA and 2-AG tissue levels within the amygdala and hippocampus and produced a sustained reduction in eCB function in the hippocampus at adulthood. CB receptor densities across all brain regions were generally found to be downregulated later in life following exposure to MS. Collectively, these data demonstrate that early life stress can alter the normative ontogeny of the eCB system, resulting in a sustained deficit in eCB function, particularly within the hippocampus, in adulthood.
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http://dx.doi.org/10.1016/j.neuropharm.2018.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347425PMC
March 2019

Recent trends in cyclic vomiting syndrome-associated hospitalisations with liberalisation of cannabis use in the state of Colorado.

Intern Med J 2019 05;49(5):649-655

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Background: Currently, 33 states in the United States along with the District of Columbia have legalised cannabis in some forms. There is a paucity of data on the impact of legalisation of cannabis use on hospitalisations due to cyclic vomiting syndrome (CVS).

Aim: To study the trends in CVS-related hospitalisations and cannabis use in CVS in relation to legalisation of recreational cannabis use in Colorado.

Methods: All hospital admissions in Colorado between 2010 and 2014 with the diagnosis of CVS were identified using the Colorado State Inpatient Database. Five-year trends in CVS-related hospitalisations along with the cannabis use were analysed. Multivariate logistic regression analysis was performed to determine predictors of cannabis use in CVS.

Results: There was a significant increase in CVS-related hospitalisations by 46% from 806 in 2010 to 1180 in 2014 when CVS was included as all-listed diagnoses (P < 0.001). The overall prevalence of cannabis use in CVS (13% with CVS as primary diagnosis and 17% with CVS as all-listed diagnoses) was much higher than non-CVS-related hospitalisations (1.7%) (P < 0.001 for both comparisons). Cannabis use increased dramatically in both CVS and non-CVS-related hospitalisations following legalisation of cannabis for recreational use in 2012.

Conclusion: Our study shows a significant increase in CVS-related hospitalisations concomitant with an increase in cannabis use with its liberalisation in Colorado. Future studies on the relationship between cannabis use and hyperemesis are warranted, especially with its ongoing legalisation in the United States.
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http://dx.doi.org/10.1111/imj.14164DOI Listing
May 2019

Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity.

Neuropsychopharmacology 2018 09 27;43(10):2017-2027. Epub 2018 Jun 27.

Department of Psychology, University of Haifa, Haifa, 3498838, Israel.

Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.
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http://dx.doi.org/10.1038/s41386-018-0135-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098035PMC
September 2018
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