Tag Archives: CB1

Anandamide and 2-AG Are Endogenously Present within the Laterodorsal Tegmental Nucleus: Functional Implications for a role of eCBs in arousal.

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“Previously, we presented electrophysiological evidence for presence in mice brain slices of functional cannabinoid type I receptors (CB1Rs) within the laterodorsal tegmentum (LDT), a brain stem nucleus critical in control of arousal and rapid eye movement (REM) sleep. Further, using pharmacological agents, we provided data suggestive of the endogenous presence of cannabinoids (CBs) acting at LDT CB1Rs. However, in those studies, we were unable to identify the type(s) of CB ligands endogenously present in the LDT, and this information has not been provided elsewhere. Accordingly, we used the highly-sensitive liquid chromatography/mass spectrometry (LC-MS) method to determine whether N-arachidonoylethanolamide (Anandamide or AEA) and 2-arachidonyl glycerol (2-AG), which are both endogenous CB ligands acting at CB1Rs, are present in the LDT. Mice brain tissue samples of the LDT were assayed using ion trap LC-MS in selected ion monitoring mode. Chromatographic analysis and product-ion MS scans identified presence of the CBs, AEA and 2-AG, from LDT mouse tissue. Data using the LC-MS method show that AEA and 2-AG are endogenously present within the LDT and when coupled with our electrophysiological findings, lead to the suggestion that AEA and 2-AG act at electropharmacologically-demonstrated CB1Rs in this nucleus. Accordingly, AEA and 2-AG likely play a role in processes governed by the LDT, including control of states of cortical gamma band activity seen in alert, aroused states, as well as cortical and motor activity characteristic of REM sleep.”

https://www.ncbi.nlm.nih.gov/pubmed/28404451

Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment

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Mary Ann Liebert, Inc. publishers

“We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).

Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.

The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
http://online.liebertpub.com/doi/full/10.1089/can.2015.0008

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

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“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.

RESULTS.:

Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.

CONCLUSION.:

‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.”

https://www.ncbi.nlm.nih.gov/pubmed/28387811

Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.

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“Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB1R). However, the underlying mechanisms are not fully understood.

Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.

Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.”

https://www.ncbi.nlm.nih.gov/pubmed/28377876

Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.

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“Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered.

The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance.

In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant.

Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine.

Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.”

https://www.ncbi.nlm.nih.gov/pubmed/28377074

Post-sensitization treatment with rimonabant blocks the expression of cocaine-induced behavioral sensitization and c-Fos protein in mice.

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“CB1 receptor antagonists have been shown to prevent acute and long-term behavioral effects of cocaine.

Here we evaluate the effectiveness of the CB1 receptor antagonist rimonabant to modify sensitized responses to cocaine.

Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse.”

https://www.ncbi.nlm.nih.gov/pubmed/28366798

[Role of cannabinoid receptor 1-mediated synaptic plasticity in neuropathic pain and associated depression].

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“Neuropathic pain is a class of pain caused by an injury or diseases of the somatosensory system and characterized by spontaneous pain, allodynia, and hyperalgesia. It is well established that central sensitization is one of the key mechanisms underlying the development and maintenance of neuropathic pain. Cannabinoid receptor 1 (CB1R) of endocannabinoid system modulates synaptic transmission, regulates synaptic plasticity, inhibits central sensitization, and thus attenuates neuropathic pain. Recent studies have shown that activation of CB1R also involves in the relief of neuropathic pain-induced depression.” https://www.ncbi.nlm.nih.gov/pubmed/28364110

The effect of cannabinoid receptor 1 blockade on hepatic free fatty acid profile in mice with nonalcoholic fatty liver disease.

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“We used rimonabant to investigate the role of CB1 receptor on hepatic FFAs profile during NAFLD. Male mice C57BL/6 were divided into: control group fed with control diet 20 weeks (C; n=6); group fed with HFD 20 weeks (HF; n=6); group fed with control diet and treated with rimonabant after 18 weeks (R; n=9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n=10). Rimonabant (10mg/kg) was administered daily to HFR and R group by oral gavage. Rimonabant decreased liver palmitic acid proportion in HFR group compared to HF group (p<0.05). Liver stearic and oleic acid proportions were decreased in R group compared to control (p<0.01 respectively). Rimonabant increased liver linoleic and arachidonic acid proportions in HFR group compared to HF group (p<0.01 respectively). CB1 blockade may be useful in the treatment of HFD-induced NAFLD due to modulation of plasma lipid and hepatic FFA profile.”  https://www.ncbi.nlm.nih.gov/pubmed/28363784

http://www.sciencedirect.com/science/article/pii/S0009308417300063

Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice.

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“Accumulating evidence suggests that cannabinoid ligands play delicate roles in cell survival and apoptosis decisions, and that cannabinoid CB1 receptors (CB1R) modulate dopaminergic function.

However, the role of CB1R in methamphetamine (MA)-induced dopaminergic neurotoxicity in vivo remains elusive.

Multiple high doses of MA increased phospho-ERK and CB1R mRNA expressions in the striatum of CB1R (+/+) mice. These increases were attenuated by CB1R antagonists (i.e., AM251 and rimonabant), an ERK inhibitor (U0126), or dopamine D2R antagonist (sulpiride).

CB1R agonist-induced toxic effects were significantly attenuated by CB1R knockout, CB1R antagonists or PKCδ knockout.

Therefore, our results suggest that interaction between D2R, ERK and CB1R is critical for MA-induced dopaminergic neurotoxicity and that PKCδ mediates dopaminergic damage induced by high-doses of CB1R agonist.”

https://www.ncbi.nlm.nih.gov/pubmed/28363605

Comparative antinociceptive effect of arachidonylcyclopropylamide, a cannabinoid 1 receptor agonist & lignocaine, a local anaesthetic agent, following direct intrawound administration in rats.

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“Treatment of inflammatory pain with opioids is accompanied by unpleasant and, at times, life-threatening side effects.

Cannabis produces antinociception as well as psychotropic effects. It was hypothesized that peripheral cannabinoid receptors outside the central nervous system could be selectively activated for relief of pain.

This study was undertaken to measure the antinociceptive effect of type 1 cannabinoid receptor (CB1r) agonist arachidonylcyclopropylamide (ACPA) in a rat model of inflammatory pain after intrawound administration and the effects were compared with lignocaine.

Lignocaine attenuated evoked pain behaviour whereas ACPA decreased guarding score. This difference was likely due to blockade of sodium ion channels and the activation of peripheral CB1r, respectively. Central side effects were absent after ACPA treatment. Further studies need to be done to assess the effect of ACPA treatment in clinical conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/28361827