Basic Science and Pathogenesis.

Background: The presence of Tau pathology is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer's disease (AD), suggesting that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as their activation is strongly related to the progression of tau phosphorylation and aggregation potentially due to dysfunctional lysosomal activity. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD.

Endocannabinoid dysregulation and PTSD in urban adolescents: Associations with anandamide concentrations and FAAH genotype.

Background: The endocannabinoid system, which regulates fear- and anxiety-related behaviors, is dysregulated in adults with posttraumatic stress disorder (PTSD), as indicated by higher circulating anandamide (AEA) concentrations. The C385A (rs324420) polymorphism in the fatty acid amide hydrolase (FAAH) gene, which catabolizes AEA, is linked to higher AEA concentrations and greater PTSD symptoms in adults. Given that adolescence is a critical period during which trauma and psychiatric disorders emerge, understanding this relationship in youth is essential.

Lack of Cannabinoid Type 2 Promoter Activity in Normal or Injured Kidneys Using a Cnr2-GFP Reporter Mouse.

Although cannabinoid type 2 (CB2) receptor activity is known to promote diverse biological functions in the kidney, published data regarding CB2 receptor protein levels and cellular distribution within the kidney is inconsistent. The goal of the present study was to investigate the changes of CB2 in the kidney obtained from mice exposed to various forms of kidney injury using a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous cannabinoid receptor 2 (Cnr2) promoter. Kidney injury was established in a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous Cnr2 promoter.

Yoga for Veterans with PTSD: Intervention Feasibility, Changes in PTSD Symptom Severity, and Psychological and Physiological Health-Related Fitness Outcomes.

Posttraumatic stress disorder (PTSD) is a burdensome disorder associated with lower quality of life and increased morbidity and mortality. Veterans are particularly at risk for PTSD resulting from experiencing traumatic events during military service. Current treatments for PTSD often fail to remediate symptoms and are associated with high dropout rates; therefore, complementary and integrative health approaches, such as yoga, are being considered to treat PTSD-related symptoms.

Endocannabinoid signaling in stress, nausea, and vomiting.

Background: Classical antiemetics that target the serotonin system may not be effective in treating certain nausea and vomiting conditions like cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS). As a result, there is a need for better therapies to manage the symptoms of these disorders, including nausea, vomiting, and anxiety. Cannabis is often used for its purported antiemetic and anxiolytic effects, given regulation of these processes by the endocannabinoid system (ECS).

Differences in intestinal bacteria in traumatic injury survivors with and without probable posttraumatic stress disorder.

Background: Posttraumatic stress disorder (PTSD) is a common consequence of traumatic injury, yet certain biological factors contributing to PTSD are poorly understood. The gut microbiome may influence mental health outcomes, but its role in heterogeneous PTSD presentations requires elucidation.

Methods: Bacterial composition was examined in adults 2-4 years post-trauma with probable PTSD (n = 24) versus trauma-exposed controls without probable PTSD (n = 24).

Cannabinoid CB receptors in primary sensory neurons are implicated in CB agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB agonists show therapeutic efficacy without unwanted CB-mediated side effects. The G protein-biased CB receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated.

Mitigating gut microbial degradation of levodopa and enhancing brain dopamine: Implications in Parkinson's disease.

Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria.

Acute and Long-Term Effects of App-Delivered Heartfulness Meditation on Psychological Outcomes and the Endocannabinoid Signaling System in Cyclic Vomiting Syndrome.

Introduction: Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction often triggered by stress. Interventions such as meditation may improve psychological outcomes and health-related quality of life (HRQoL), but their efficacy and the underlying mechanism are unknown.

Methods: We conducted a 6-week single-arm pilot study to assess the effects of heartfulness meditation (HFM) in CVS using a custom-designed meditation app.

Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease.

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation.

Cannabinoid CB receptors in primary sensory neurons are implicated in CB agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance.

Cannabinoid CB agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB receptors. The G protein-biased CB receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood.

Dysfunction in endocannabinoids, palmitoylethanolamide, and degradation of tryptophan into kynurenine in individuals with depressive symptoms.

Background: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways.

Endocannabinoid and psychological responses to acute resistance exercise in trained and untrained adults.

Introduction: This study examined the effects of acute resistance exercise on circulating endocannabinoid (eCB) and mood responses in trained and untrained healthy adults.

Methods: Thirty-two healthy adults (22.1 ± 2.

Endocannabinoids, cortisol, and development of post-traumatic psychopathological trajectories.

Objective: Our prior published work using the 2-factor model of PTSD identified four subgroups of trauma survivors on average 6 months following trauma: Resilient, Dysphoria, High Comorbid, and Severe Comorbid. Some findings indicate that low and high cortisol responses may increase risk for the development of PTSD and depression respectively, yet ways in which cortisol interacts with other physiological systems to enhance risk is unclear. This study examined the role of circulating eCBs in the development of previously identified psychopathological trajectories that is differentiated by cortisol in traumatically injured adults (N = 169).

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis.

MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION.

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation.

Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain.

CB cannabinoid receptor agonists suppress pathological pain in animal models and lack unwanted side effects commonly associated with direct activation of CB receptors. However, the types of pain most responsive to CB agonists are incompletely understood and cell types which underlie CB-mediated therapeutic efficacy remain largely unknown. We previously reported that the CB receptor agonist LY2828360 reduced neuropathic nociception induced by toxic challenge with chemotherapeutic and anti-retroviral agents in mice.

Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats.

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration escalates intake in male rats.

FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats.

Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic ( and ) and endocannabinoid (, and ) targets in the mPFC following ELS and pharmacological treatment.

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease.

The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB receptor. In Alzheimer's disease (AD), amyloid beta (Aβ)-containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown.

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy.

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 - ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2',3'-dideoxycytidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance.

Endocannabinoid signaling in the central nervous system.

It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior.