International Journal of Molecular Sciences

Research

14 pages, 4726 KiB

Open AccessArticle

Heteromers Formed by GPR55 and Either Cannabinoid CB₁ or CB₂ Receptors Are Upregulated in the Prefrontal Cortex of Multiple Sclerosis Patients

by Carlota Menéndez-Pérez, Rafael Rivas-Santisteban, Eva del Valle, Jorge Tolivia, Ana Navarro, Rafael Franco and Eva Martínez-Pinilla

Int. J. Mol. Sci. 2024, 25(8), 4176; https://doi.org/10.3390/ijms25084176 - 10 Apr 2024

Viewed by 404

Abstract

Multiple sclerosis (MS) is an autoimmune, inflammatory, and neurodegenerative disease of the central nervous system for which there is no cure, making it necessary to search for new treatments. The endocannabinoid system (ECS) plays a very important neuromodulatory role in the CNS. In [...] Read more.

Multiple sclerosis (MS) is an autoimmune, inflammatory, and neurodegenerative disease of the central nervous system for which there is no cure, making it necessary to search for new treatments. The endocannabinoid system (ECS) plays a very important neuromodulatory role in the CNS. In recent years, the formation of heteromers containing cannabinoid receptors and their up/downregulation in some neurodegenerative diseases have been demonstrated. Despite the beneficial effects shown by some phytocannabinoids in MS, the role of the ECS in its pathophysiology is unknown. The main objective of this work was to identify heteromers of cell surface proteins receptive to cannabinoids, namely GPR55, CB₁ and CB₂ receptors, in brain samples from control subjects and MS patients, as well as determining their cellular localization, using In Situ Proximity Ligation Assays and immunohistochemical techniques. For the first time, CB₁R-GPR55 and CB₂R-GPR55 heteromers are identified in the prefrontal cortex of the human brain, more in the grey than in the white matter. Remarkably, the number of CB₁R-GPR55 and CB₂R-GPR55 complexes was found to be increased in MS patient samples. The results obtained open a promising avenue of research on the use of these receptor complexes as potential therapeutic targets for the disease. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

17 pages, 5696 KiB

Open AccessArticle

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum

by Louise Adermark, Rosita Stomberg, Bo Söderpalm and Mia Ericson

Int. J. Mol. Sci. 2024, 25(1), 581; https://doi.org/10.3390/ijms25010581 - 01 Jan 2024

Cited by 1 | Viewed by 958

Abstract

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting [...] Read more.

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Graphical abstract

12 pages, 675 KiB

Open AccessCommunication

Plasma Endocannabinoid Levels in Patients with Borderline Personality Disorder and Healthy Controls

by Jennifer Spohrs, Valentin Kühnle, David Mikusky, Niklas Sanhüter, Ana Macchia, Sandra Nickel and Birgit Abler

Int. J. Mol. Sci. 2023, 24(24), 17452; https://doi.org/10.3390/ijms242417452 - 14 Dec 2023

Viewed by 920

Abstract

Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder and presents a complex therapeutic challenge due to limited treatment modalities. Recent focus has converged on the endocannabinoid system (ECS) as a prospective modulator of psychopathological processes in BPD. To address this hypothesis, [...] Read more.

Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder and presents a complex therapeutic challenge due to limited treatment modalities. Recent focus has converged on the endocannabinoid system (ECS) as a prospective modulator of psychopathological processes in BPD. To address this hypothesis, we analysed plasma endocannabinoid concentrations, specifically anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in a cohort of 49 female BPD patients and 32 matched healthy controls (HC). Additionally, we examined the effect of the FAAH polymorphism rs324420 and correlates with psychopathology. The results indicate heightened AEA levels and, by trend, augmented 2-AG levels within the patient group, as compared to the HC group. Significant between group differences in AEA levels were evident in the CC genotype (FAAH_rs324420) but not in A-allele carriers while the commonly observed difference in AEA levels between A-allele carriers as compared to the CC genotype was not evident in patients. An effect of genotype was found with higher ratings of depression (Beck’s depression inventory, BDI-II) in the CC genotype compared to A-allele carriers (FAAH_rs32442), particularly in the patients. Significant alterations in AEA (and by trend in 2-AG) in patients with BPD may relate to compensatory ECS activity. The finding that the effect is most pronounced in CC homozygotes, might point towards a countermeasure to balance physiologically lower baseline AEA levels. The findings warrant further research to develop potentially beneficial psychopharmacological therapies. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

18 pages, 17254 KiB

Open AccessArticle

Expression of Cannabinoid Receptors in the Trigeminal Ganglion of the Horse

by Rodrigo Zamith Cunha, Alberto Semprini, Giulia Salamanca, Francesca Gobbo, Maria Morini, Kirstie J. Pickles, Veronica Roberts and Roberto Chiocchetti

Int. J. Mol. Sci. 2023, 24(21), 15949; https://doi.org/10.3390/ijms242115949 - 03 Nov 2023

Viewed by 1086

Abstract

Cannabinoid receptors are expressed in human and animal trigeminal sensory neurons; however, the expression in the equine trigeminal ganglion is unknown. Ten trigeminal ganglia from five horses were collected post-mortem from an abattoir. The expression of cannabinoid receptors type 1 (CB1R) and type [...] Read more.

Cannabinoid receptors are expressed in human and animal trigeminal sensory neurons; however, the expression in the equine trigeminal ganglion is unknown. Ten trigeminal ganglia from five horses were collected post-mortem from an abattoir. The expression of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and the cannabinoid-related receptors like transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARɣ), and G protein-related receptor 55 (GPR55) in the trigeminal ganglia (TG) of the horse were studied, using immunofluorescence on cryosections and formalin-fixed paraffin-embedded (FFPE) sections. Neurons and glial cells were identified using fluorescent Nissl staining NeuroTrace^® and an antibody directed against the glial marker glial fibrillary acidic protein (GFAP), respectively. Macrophages were identified by means of an antibody directed against the macrophages/microglia marker ionized calcium-binding adapter molecule 1 (IBA1). The protein expression of CB1R, CB2R, TRPV1, and PPARɣ was found in the majority of TG neurons in both cryosections and FFPE sections. The expression of GPR55 immunoreactivity was mainly detectable in FFPE sections, with expression in the majority of sensory neurons. Some receptors were also observed in glial cells (CB2R, TRPV1, PPARγ, and GPR55) and inflammatory cells (PPARγ and GPR55). These results support further investigation of such receptors in disorders of equine trigeminal neuronal excitability. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

21 pages, 2992 KiB

Open AccessArticle

Long-Term Treatment with Cannabidiol-Enriched Cannabis Extract Induces Synaptic Changes in the Adolescent Rat Hippocampus

by Andrey F. L. Aguiar, Raquel M. P. Campos, Alinny R. Isaac, Yolanda Paes-Colli, Virgínia M. Carvalho, Luzia S. Sampaio and Ricardo A. de Melo Reis

Int. J. Mol. Sci. 2023, 24(14), 11775; https://doi.org/10.3390/ijms241411775 - 21 Jul 2023

Cited by 1 | Viewed by 1612

Abstract

The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), [...] Read more.

The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

Review

Jump to: Research, Other

19 pages, 610 KiB

Open AccessReview

Beta-Caryophyllene, a Cannabinoid Receptor Type 2 Selective Agonist, in Emotional and Cognitive Disorders

by Caterina Ricardi, Serena Barachini, Giorgio Consoli, Donatella Marazziti, Beatrice Polini and Grazia Chiellini

Int. J. Mol. Sci. 2024, 25(6), 3203; https://doi.org/10.3390/ijms25063203 - 11 Mar 2024

Viewed by 951

Abstract

Mental disorders account for one of the most prevalent categories of the burden of disease worldwide, with depression expected to be the largest contributor by 2030, closely followed by anxiety. The COVID-19 pandemic possibly exacerbated these challenges, especially amongst adolescents, who experienced isolation, [...] Read more.

Mental disorders account for one of the most prevalent categories of the burden of disease worldwide, with depression expected to be the largest contributor by 2030, closely followed by anxiety. The COVID-19 pandemic possibly exacerbated these challenges, especially amongst adolescents, who experienced isolation, disrupted routines, and limited healthcare access. Notably, the pandemic has been associated with long-term neurological effects known as “long-COVID”, characterized by both cognitive and psychopathological symptoms. In general, psychiatric disorders, including those related to long-COVID, are supposed to be due to widespread inflammation leading to neuroinflammation. Recently, the endocannabinoid system (ECS) emerged as a potential target for addressing depression and anxiety pathophysiology. Specifically, natural or synthetic cannabinoids, able to selectively interact with cannabinoid type-2 receptor (CB2R), recently revealed new therapeutic potential in neuropsychiatric disorders with limited or absent psychotropic activity. Among the most promising natural CB2R ligands, the bicyclic sesquiterpene β-caryophyllene (BCP) has emerged as an excellent anti-inflammatory and antioxidant therapeutic agent. This review underscores BCP’s immunomodulatory and anti-inflammatory properties, highlighting its therapeutic potential for the management of depression and anxiety. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

18 pages, 3243 KiB

Open AccessReview

Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease

by Juan F. Osuna-Ramos, Josué Camberos-Barraza, Laura E. Torres-Mondragón, Ángel R. Rábago-Monzón, Alejandro Camacho-Zamora, Marco A. Valdez-Flores, Carla E. Angulo-Rojo, Alma M. Guadrón-Llanos, Verónica J. Picos-Cárdenas, Loranda Calderón-Zamora, Javier A. Magaña-Gómez, Claudia D. Norzagaray-Valenzuela, Feliznando I. Cárdenas-Torres and Alberto K. De la Herrán-Arita

Int. J. Mol. Sci. 2023, 24(24), 17458; https://doi.org/10.3390/ijms242417458 - 14 Dec 2023

Cited by 1 | Viewed by 1559

Abstract

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system [...] Read more.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain’s extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

25 pages, 1775 KiB

Open AccessReview

Anxiety Modulation by Cannabinoids—The Role of Stress Responses and Coping

by József Haller

Int. J. Mol. Sci. 2023, 24(21), 15777; https://doi.org/10.3390/ijms242115777 - 30 Oct 2023

Cited by 1 | Viewed by 1978

Abstract

Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, [...] Read more.

Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, and discrepant findings obtained with various experimental approaches makes the interpretation of research results difficult. Here, we review the anxiety-related effects of the three main interventions used to study the endocannabinoid system: pharmacological agents active at endocannabinoid-binding sites present on both the cell membrane and in the cytoplasm, genetic manipulations targeting cannabinoid receptors, and function-enhancers represented by inhibitors of endocannabinoid degradation and transport. Binding-site ligands provide inconsistent findings probably because they activate a multitude of mechanisms concomitantly. More robust findings were obtained with genetic manipulations and particularly with function enhancers, which heighten ongoing endocannabinoid activation rather than affecting all mechanisms indiscriminately. The enhancement of ongoing activity appears to ameliorate stress-induced anxiety without consistent effects on anxiety in general. Limited evidence suggests that this effect is achieved by promoting active coping styles in critical situations. These findings suggest that the functional enhancement of endocannabinoid signaling is a promising drug development target for stress-related anxiety disorders. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

► Show Figures

Figure 1

Other

Jump to: Research, Review

12 pages, 283 KiB

Open AccessOpinion

Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials

by Martina D’Angelo and Luca Steardo, Jr.

Int. J. Mol. Sci. 2024, 25(7), 3603; https://doi.org/10.3390/ijms25073603 - 22 Mar 2024

Viewed by 617

Abstract

The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management [...] Read more.

The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management of sleep disorders. THC, the psychoactive component of cannabis, may initially promote sleep, but, in the long term, alters sleep architecture, while CBD shows promise in improving sleep quality without psychoactive effects. Clinical studies suggest that CBD modulates endocannabinoid signaling through several receptor sites, offering a multifaceted approach to sleep regulation. Similarly, palmitoylethanolamide (PEA), in addition to interacting with the endocannabinoid system, acts as an agonist on peroxisome proliferator-activated receptors (PPARs). The favorable safety profile of CBD and PEA and the potential for long-term use make them an attractive alternative to conventional pharmacotherapy. The integration of the latter two compounds into comprehensive treatment strategies, together with cognitive–behavioral therapy for insomnia (CBT-I), represents a holistic approach to address the multifactorial nature of sleep disorders. Further research is needed to establish the optimal dosage, safety, and efficacy in different patient populations, but the therapeutic potential of CBD and PEA offers hope for improved sleep quality and general well-being. Full article

(This article belongs to the Special Issue Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology)

Journal Menu

Journal Browser

Mechanisms of the Endocannabinoid System and Their Role in Neurophysiology and Psychopathology

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI