The spatiotemporal expression of cannabinoid receptors and endocannabinoid‐metabolising enzymes during brain development guides major developmental processes including neurogenesis, cell differentiation, cell migration, neuronal specification and synaptogenesis.
Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment. 相似文献
Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. 相似文献
Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms. 相似文献
Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250–100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis. 相似文献
Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders. 相似文献
The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate; WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N = 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ9-tetrahydrocannabinol; THC) were also found to have increased levels of SYNGAP1 in the PFC. THC exposure also led to a pronounced upregulation of SYNGAP1 in the amygdala, but without any changes in the dorsal striatum, hippocampus, or nucleus accumbens. To our knowledge, this is the first study to uncover a link between cannabinoid exposure and changes in SYNGAP1 that are spatio-temporal and developmental in nature. Future studies are needed to investigate the putative role of SYNGAP1 in the negative behavioral consequences of cannabis use in adolescence. 相似文献
Rosacea is a common chronic cutaneous inflammatory disorder. Recently, patients with rosacea were identified as having a higher risk of developing various comorbidities such as cardiovascular disease, psychiatric disorders, neurologic disorders, and gastrointestinal disorders. However, the risks of some comorbidities in patients with rosacea are somewhat contradictory, depending upon the study design. Moreover, pathomechanisms associated with the comorbidities of patients with rosacea remain poorly elucidated. The purpose of this review was to provide the most up-to-date evidence on the risks of neuropsychiatric and gastrointestinal comorbidities in patients with rosacea. Moreover, the molecular pathomechanisms associated with neuropsychiatric and gastrointestinal comorbidities in patients with rosacea were evaluated based on recent studies. This review was also intended to focus more on the role of the gut–brain–skin axis in the association of neuropsychiatric and gastrointestinal comorbidities in rosacea. 相似文献
Endocannabinoid (eCB) signaling is markedly decreased in the hippocampus (Hip) of aged mice, and the genetic deletion of the cannabinoid receptor type 1 (CB1) leads to an early onset of cognitive decline and age-related histological changes in the brain. Thus, it is hypothesized that cognitive aging is modulated by eCB signaling through CB1. In the present study, we detailed the changes in the eCB system during the aging process using different complementary techniques in mouse brains of five different age groups, ranging from adolescence to old age. Our findings indicate that the eCB system is most strongly affected in middle-aged mice (between 9 and 12 months of age) in a brain region-specific manner. We show that 2-arachidonoylglycerol (2-AG) was prominently decreased in the Hip and moderately in caudate putamen (CPu), whereas anandamide (AEA) was decreased in both CPu and medial prefrontal cortex along with cingulate cortex (mPFC+Cg), starting from 6 months until 12 months. Consistent with the changes in 2-AG, the 2-AG synthesizing enzyme diacylglycerol lipase α (DAGLα) was also prominently decreased across the sub-regions of the Hip. Interestingly, we found a transient increase in CB1 immunoreactivity across the sub-regions of the Hip at 9 months, a plausible compensation for reduced 2-AG, which ultimately decreased strongly at 12 months. Furthermore, quantitative autoradiography of CB1 revealed that [3H]CP55940 binding markedly increased in the Hip at 9 months. However, unlike the protein levels, CB1 binding density did not drop strongly at 12 months and at old age. Furthermore, [3H]CP55940 binding was significantly increased in the lateral entorhinal cortex (LEnt), starting from the middle age until the old age. Altogether, our findings clearly indicate a middle-age crisis in the eCB system, which could be a potential time window for therapeutic interventions to abrogate the course of cognitive aging. 相似文献
WOBE437 ((2E,4E)-N-(3,4-dimethoxyphenethyl)dodeca-2,4-dienamide, 1 ) is a natural product-derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 ( 1 ). At the same time, a number of WOBE437 variants exhibited potencies in the sub-100 nM range, with high selectivity over inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1 . Interestingly, profound activity differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug-like properties. 相似文献
There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis is harmless. At the same time, studies suggest that cannabinoids may have therapeutic potential against the impacts of stress on the brain and behavior, and that young people sometimes use cannabinoids to alleviate feelings of depression and anxiety (i.e., “self-medication”). Exposure to early adverse life events may predispose individuals to developing psychopathology in adulthood, leading researchers to study the causality between early life factors and cognitive and emotional outcomes in rodent models and to probe the underlying mechanisms. In this review, we aim to better understand the long-term effects of cannabinoids administered in sensitive developmental periods (mainly adolescence) in rodent models of early life stress. We suggest that the effects of cannabinoids on emotional and cognitive function may vary between different sensitive developmental periods. This could potentially affect decisions regarding the use of cannabinoids in clinical settings during the early stages of development and could raise questions regarding educating the public as to potential risks associated with cannabis use. 相似文献
Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging. Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs. Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders. 相似文献
Psoriasis is a chronic inflammatory skin disease with systemic manifestation, in which psychological factors play an important role. The etiology of psoriasis is complex and multifactorial, including genetic background and environmental factors such as emotional or physical stress. Psychological stress may also play a role in exacerbation of psoriasis, by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic–adrenal–medullary axis, peripheral nervous system, and immune system. Skin cells also express various neuropeptides and hormones in response to stress, including the fully functional analog of the HPA axis. The deterioration of psoriatic lesions is accompanied by increased production of inflammatory mediators, which could contribute to the imbalance of neurotransmitters and the development of symptoms of depression and anxiety. Therefore, deregulation of the crosstalk between endocrine, paracrine, and autocrine stress signaling pathways contributes to clinical manifestations of psoriasis, which requires multidisciplinary approaches. 相似文献
The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51 has repeatedly been associated with emotion processing and numerous stress-related affective disorders. It has also been implicated in contributing to the glucocorticoid hyposensitivity observed in New World primates. More recently, several research groups have consistently shown a protective effect of FKBP51 knockout or knockdown on stress endocrinology and stress-coping behavior in animal models of depression and anxiety. The principal druggability of FKBP51 is exemplified by the prototypic FKBP ligands FK506 and rapamycin. Moreover, FKBP51 is highly suited for X-ray co-crystallography, which should facilitate the rational drug design of improved FKBP51 ligands. In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery. 相似文献
Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy. 相似文献
The excessive activation of microglia cell induced by adolescent intermittent ethanol (AIE) leads to neuroinflammation in the hippocampus. The endocannabinoid system plays a key role in the modulation of microglia activation. Accumulating evidence suggests that regular exercise improves learning and memory deficits in AIE models. The purpose of this study was to explore the effects of treadmill exercise intervention on the cognitive performance, activation of microglia cells and the expression of monoacylglycerol lipase (MAGL), cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) in the hippocampus of AIE rats. Here, we show that AIE rats exhibited cognitive impairments, whereas the treadmill exercise improves the cognitive performance in AIE rats. In order to explore the possible mechanisms for the exercise-induced attenuation of cognitive disorder, we examined the neuroinflammation in the hippocampus. We found that treadmill exercise led to the decrease in the level of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and the increase in the level of anti-inflammatory cytokine (IL-10). In addition, we found that treadmill exercise reduced the excessive activation of the microglia cell in the hippocampus of AIE rats. Finally, we found that AIE led to a decrease in the expression of CB1R and CB2R in the hippocampus; however, the treadmill exercise further decreased the expression of CB2R in the hippocampus of AIE rats. Our results suggest that treadmill exercise attenuates AIE-induced neuroinflammation and the excessive activation of hippocampus microglial cells, which may contribute to the exercise-induced improvement of cognitive performance in AIE rats. 相似文献
The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS. It is implicated in a variety of physiological and pathological states and an attractive pharmacological target yet to reach its full potential. This review will focus on the involvement of ECS in glucose and lipid metabolism, food intake regulation, immune homeostasis, respiratory health, inflammation, cancer and other physiological and pathological states will be substantiated using freely available data from open-access databases, experimental data and literature review. Future directions should envision capturing its diversity and exploiting pharmacological options beyond the classical ECS suspects (exogenous cannabinoids and cannabinoid receptor monomers) as signaling through cannabinoid receptor heteromers offers new possibilities for different biochemical outcomes in the cell. 相似文献
It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain. 相似文献
