Immunohistochemical analysis of cannabinoid receptor 1 expression in steatotic rat livers.

“The primary aim of the present study was to determine the expression levels of cannabinoid receptor type 1 (CB1) in steatotic rat livers.  The secondary aim was to clarify whether steatosis and inflammation are more marked in areas with increased CB1 overexpression.

The expression of CB1 and the number of cells overexpressing CB1 were determined. Steatosis was scored according to the Dixon scoring system.

CB1 overexpression and steatosis were detected in hepatocytes from all 38 livers sampled. The expression of CB1 was more marked in hepatocytes localized next to portal triads. Near the central veins, the expression was significantly weaker. Steatosis was more marked in areas of increased CB1 overexpression. Lymphocyte infiltration was more commonly observed in areas of increased CB1 overexpression.

Therefore, the present results indicate that CB1 receptors are overexpressed in areas with steatosis, and indicate that CB1 in hepatocytes contributes to the formation of steatosis in rats, even prior to its progression to steatohepatitis.

These results are consistent with publications reporting that CB1 in hepatocytes increases lipogenesis and contributes to inflammation.”

The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior.

“Cannabinoid receptor 1 (CB(1)) agonists usually induce dose-dependent biphasic effects on anxiety-related responses. Low doses induce anxiolytic-like effects, whereas high doses are ineffective or anxiogenic, probably due to activation of Transient Receptor Potential Vanilloid Type 1 (TRPV(1)) channels.

 In this study we have investigated this hypothesis by verifying the effects of the CB(1)/TRPV(1) agonist ACEA injected into the prelimbic medial prefrontal cortex (PL) and the participation of endocannabinoids in the anxiolytic-like responses induced by TRPV(1) antagonism, using the elevated plus-maze (EPM) and the Vogel conflict test (VCT). Moreover, we verified the expression of these receptors in the PL by double labeling immunofluorescence. ACEA induced anxiolytic-like effect in the intermediate dose, which was attenuated by previous injection of AM251, a CB(1) receptor antagonist. The higher and ineffective ACEA dose caused anxiogenic- and anxiolytic-like effects, when injected after AM251 or the TRPV(1) antagonist 6-iodonordihydrocapsaicin (6-I-CPS), respectively. Higher dose of 6-I-CPS induced anxiolytic-like effects both in the EPM and the VCT, which were prevented by previous administration of AM251. In addition, immunofluorescence showed that CB(1) and TRPV(1) receptors are closely located in the PL.

These results indicate that the endocannabinoid and endovanilloid systems interact in the PL to control anxiety-like behavior.”

Predator threat stress promotes long lasting anxiety-like behaviors and modulates synaptophysin and CB1 receptors expression in brain areas associated with PTSD symptoms.

“Several studies have suggested that changes in hippocampal, prefrontal cortex and amygdaloid complex function are associated with the main symptoms of Posttraumatic Stress Disorder (PTSD). Predator exposure can mimic some aspects of PSTD such as hyperarousal and chronic anxiety…

 The present work evaluated whether the long lasting behavioral effects evoked by predator exposure are associated to long-term changes in the expression of the Cannabinoid receptor 1 (CB1) and the synaptic protein SYP in brain areas…

 Our results suggested that predator exposure causes long-lasting anxiogenic effects associated with hyperactivation of amygdaloid complex and modulation of CB1 receptor in brain areas related to PTSD symptoms.”

Depression in Parkinson’s disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1).


“Depression is a common symptom in Parkinson’s disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher’s exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.”

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

“Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS)…

Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXSand identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

In conclusion, this is the first study addressing endocannabinoid system in a model of FXS. Our results show that dysfunctional mGlu5R signaling leads to abnormal 2-AG metabolism and physiological activity, and indicate that inhibition of 2-AG synthesis or activity at CB1Rs might be a useful treatment option in FXS patients. In this respect, recent investigations suggest that this modulation could be achieved not only by direct pharmacological blockade of CB1Rs, but also indirectly, for example through the inhibition of anandamide degradation or the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels. These two components of the endocannabinoid system, in fact, have been shown to selectively interact with mGlu5R/2-AG coupling in striatal neurons, and might interfere with the synaptic alterations seen after FMRP ablation with less side effects than those of widespread pharmacological inhibition of CB1Rs, which control not only GABA but also glutamate synapses.”

Hepatitis C Virus Induces the Cannabinoid Receptor 1

  “Chronic Hepatitis C (CHC) is one of the most common causes of hepatic fibrosis and cirrhosis with the World Health Organization (WHO) estimating that up to 3% (180 million people) of the world’s population are affected.”


“CB1 is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus.”

“There has been much recent interest in the use of CB1 antagonists to treat both hepatic and metabolic disease and our findings emphasize the likely usefulness of these compounds in patients with hepatitis C. In addition to the amelioration of steatosis and fibrosis, CB1 blockade reduces portal pressure and can reverse mesenteric arterial dilatioN, making them useful in end stage liver disease as well.”


“Cannabis (Cannabis Sativa, marijuana) has been used for medicinal and ritual purposes for over 3 millennia, and remains the most commonly used recreational drug in the western world. The identification of the cannabinoid receptor 1 (CB1) in human brain some twenty years ago and the subsequent discovery of endogenous cannabinoids, has led to an understanding of the importance of the endocannabinoid system in health and disease.”

Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation

 “Exposure to stress elicits excitoxicity and neuroinflammation in the brain, contributing to cell death and damage in stress-related neurological and neuropsychiatric diseases. The endocannabinoid system is present in stress-responsive neural circuits and has been proposed as an endogenous neuroprotective system activated in some neuropathological scenarios to restore homeostasis. To elucidate the possible regulatory role of cannabinoid receptor 1 (CB1) in stress-induced excitotoxicity and neuroinflammation, both genetic and pharmacological approaches were used alternatively… These multifaceted neuroprotective effects suggest that CB1 activation could be a new therapeutic strategy against neurological/neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

“Antiinflammatory Effects Elicited by CB1 Activation. Mechanisms Involved”

“In general, ECS has been proposed as an endogenous protective system against excessive inflammatory/immune responses in multiple CNS pathologies. Our following studies were aimed at clarifying the particular role of CB1 as a possible regulator of stress-induced inflammatory response.”

“In summary, the multifaceted neuroprotective effects described here suggest that CB1 activation is an attractive therapeutic strategy against diverse neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial.


“Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.”

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

“Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis (cell death) in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children…

 Our study shows that treatment with the cannabinoid receptor agonists HU210 (cloned THC from Hebrew University) and Delta(9)-tetrahydrocannabinol (THC from cannabis) lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis…

These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.”

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