Tag Archives: cannabinoid receptors

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.

Posted on by
Reply

“Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories.

We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation.

Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved.

Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH+ cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation.

Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/27528659

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis.

Posted on by
Reply

“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis.

CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

For multifactorial chronic diseases, such as fibrosis, the conventional pharmacological approach based on the “one-disease/one-target/one-drug” paradigm limits therapeutic efficacy and could be improved by simultaneously hitting multiple therapeutic targets.

One such target is the endocannabinoid/cannabinoid-1 receptor (endocannabinoid/CB1R) system.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases .

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979564/

Endocannabinoid dysregulation in cognitive and stress-related brain regions in the Nrg1 mouse model of schizophrenia.

Posted on by
Reply

 

“The endocannabinoid system is dysregulated in schizophrenia.

These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain.

Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippocampus to impair cognition in schizophrenia, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry.”

http://www.ncbi.nlm.nih.gov/pubmed/27521758

Metabolism of endocannabinoids.

Posted on by
Reply

“Endocannabinoids belong to a group of ester, ether and amide derivatives of fatty acids, which are endogenous ligands of receptors CB1, CB2, TRPV1 and GPR55 that are included in the endocannabinoid system of the animal organism. The best known endocannabinoids are: N-arachidonylethanolamide called anandamide (AEA) and 2-arachidonoylglycerol (2-AG). They occur in all organisms, and their highest level is observed in the brain. In this review the mechanisms of synthesis and degradation of both AEA and 2-AG are shown. Endocannabinoids are synthesized from phospholipids (mainly phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol) located in the cell membrane. As a result of arachidonic acid transfer from phosphatidylcholine to phosphatidylethanolamine, N-arachidonoyl phosphatidylethanolamine is formed, which is hydrolyzed to AEA by phospholipase D, C and A2. However, 2-AG is formed during the hydrolysis of phosphatidylinositol catalyzed mainly by DAGL. The primary role of endocannabinoids is the activation of cannabinoid receptors. Both AEA and 2-AG are primarily agonists of the CB1 receptor and to a lower degree CB2 and TRPV1r eceptors, but 2-AG has stronger affinity for these receptors. Through activation of receptors, endocannabinoids affect cellular metabolism and participate in the metabolic processes by receptor-independent pathways. Endocannabinoids which are not bound to the receptors are degraded. The main enzymes responsible for the hydrolysis of AEA and 2-AG are FAAH and MAGL, respectively. Apart from hydrolytic degradation, endocannabinoids may also be oxidized by cyclooxygenase-2, lipoxygenases, and cytochrome P450. It has been shown that the metabolites of both endocannabinoids also have biological significance.”

http://www.ncbi.nlm.nih.gov/pubmed/27516570

CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a.

Posted on by
Reply

“The CB1 cannabinoid receptor is a G-protein coupled receptor that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection.

We report the discovery of two structurally related CB1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB1. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans, and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b seems to be unique to primates.

CRIP1a coimmunoprecipitates with CB1receptors derived from rat brain homogenates, indicating that CRIP1a and CB1 interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB1-mediated tonic inhibition of voltage-gated Ca2+ channels.

Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB1 activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).”

http://www.ncbi.nlm.nih.gov/pubmed/17895407

Cannabinoid receptor activation inhibits cell cycle progression by modulating 14-3-3β.

Posted on by
Reply

“Cannabinoids display various pharmacological activities, including tumor regression, anti-inflammatory and neuroprotective effects.

To investigate the molecular mechanisms underlying the pharmacological effects of cannabinoids, we used a yeast two-hybrid system to screen a mouse brain cDNA library for proteins interacting with type 1 cannabinoid receptor (CB1R). Using the intracellular loop 3 of CB1R as bait, we identified 14-3-3β as an interacting partner of CB1R and confirmed their interaction using affinity-binding assays. 14-3-3β has been reported to induce a cell cycle delay at the G2/M phase.

We tested the effects of cannabinoids on cell cycle progression in HeLa cells synchronized using a double-thymidine block-and-release protocol and found an increase in the population of G2/M phase cells. We further found that CB1R activation augmented the interaction of 14-3-3β with Wee1 and Cdc25B, and promoted phosphorylation of Cdc2 at Tyr-15.

These results suggest that cannabinoids induce cell cycle delay at the G2/M phase by activating 14-3-3β.”

http://www.ncbi.nlm.nih.gov/pubmed/25002257

Cannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells.

Posted on by
Reply

“CB1 cannabinoid receptors (CB1R) are one of the most abundantly expressed G protein coupled receptors (GPCR) in the CNS and regulate diverse neuronal functions.

The identification of GPCR interacting proteins has provided additional insight into the fine-tuning and regulation of numerous GPCRs.

The cannabinoid receptor interacting protein 1a (CRIP1a) binds to the distal carboxy terminus of CB1R, and has been shown to alter CB1R-mediated neuronal function.

The mechanisms by which CRIP1a regulates CB1R activity have not yet been identified; therefore the focus of this investigation is to examine the cellular effects of CRIP1a on CB1R signaling using neuronal N18TG2 cells stably transfected with CRIP1a over-expressing and CRIP1a knockdown constructs.

These studies suggest a mechanism by which endogenous levels of CRIP1a modulate CB1R-mediated signal transduction by facilitating a Gi/o protein subtype preference for Gi1 and Gi2, accompanied by an overall suppression of G-protein-mediated signaling in neuronal cells.”

http://www.ncbi.nlm.nih.gov/pubmed/25446256

Cannabinoid Receptor Interacting Protein (CRIP1a) suppresses agonist-driven CB1 receptor internalization, and regulates receptor replenishment in an agonist-biased manner.

Posted on by
Reply

“Cannabinoid Receptor Interacting Protein1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization.

In the present study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking.

These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: attenuating agonist-mediated but not internalization in the absence of exogenous agonists, and biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.”

http://www.ncbi.nlm.nih.gov/pubmed/27513693

Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging.

Posted on by
Reply

“Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low.”

http://www.ncbi.nlm.nih.gov/pubmed/27512365

The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.

Posted on by
Reply

“Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs.

To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days.

In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects.

These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27512006