Tag Archives: cannabinoid receptor

Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells

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Journal of Neuro-Oncology

“Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM).

We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Delta(9)-tetrahydrocannabinol Delta(9)-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy.

We discovered that Delta(9)-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Delta(9)-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Delta(9)-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation.

The same concentration of Delta(9)-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Delta(9)-THC.”

https://www.ncbi.nlm.nih.gov/pubmed/16078104

https://link.springer.com/article/10.1007%2Fs11060-004-5950-2

Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance

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Abstract

“Type-1 cannabinoid receptor (CB1) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB1 and its endogenous agonists, the so-called ‘endocannabinoids (eCBs)’, belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB1 signalling in vitro and on CB1-dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB1, and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB1.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165948/

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

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“The number of activated microglia increase during normal aging. Stimulation of endocannabinoid receptors can reduce the number of activated microglia, particularly in the hippocampus, of young rats infused chronically with lipopolysaccharide (LPS). In the current study we demonstrate that endocannabinoid receptor stimulation by administration of WIN-55212-2 (2 mg/kg/day) can reduce the number of activated microglia in hippocampus of aged rats and attenuate the spatial memory impairment in the water pool task. Our results suggest that the action of WIN-55212-2 does not depend upon a direct effect upon microglia or astrocytes but is dependent upon stimulation of neuronal cannabinoid receptors. Aging significantly reduced cannabinoid type 1 receptor binding but had no effect on cannabinoid receptor protein levels. Stimulation of cannabinoid receptors may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer’s disease.”

“Our results are consistent with the hypothesis that CB receptors on hippocampal neurons modulate glutamatergic and GABAergic function and this leads to reduced microglia activation. This mechanism may underlie the neuroprotective effects of cannabinoids”.

“Importantly, the benefits of cannabinoid receptor stimulation occurred at a dose that did not impair performance in a spatial memory task, indeed the performance of aged rats was significantly improved. This finding is particularly relevant for elderly for patients suffering with diseases associated with brain inflammation, e.g. AD, Parkinson’s disease or multiple sclerosis. The current report is the first to our knowledge to demonstrate the anti-inflammatory actions of cannabinoid therapy in aged animals and strongly advocate an cannabinoid-based therapy for neuroinflammation-related diseases, as well as a potential tool to reduce the impairment in memory processes occurring during normal aging.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586121/

Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention?

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Abstract

“Background

Alzheimer’s disease has become a growing socio-economical concern in developing countries where increased life expectancy is leading to large aged populations. While curing Alzheimer’s disease or stopping its progression does not appear within reach in a foreseeable future, new therapies capable of delaying the pathogenesis would represent major breakthroughs.

Presentation of the hypothesis

The growing number of medical benefits of cannabinoids, such as their ability to regulate age-related processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of AD.

Testing the hypothesis

To test this hypothesis, epidemiological studies on long term, chronic cannabinoid users could enlighten us on the potential benefits of these compounds in normal and pathological ageing processes. Systematic pharmacological (and thus more mechanistic) investigations using animal models of Alzheimer’s disease that have been developed would also allow a thorough investigation of the benefits of cannabinoid pharmacotherapy in the pathogenesis of Alzheimer’s disease.

Implications of the hypothesis

The chronic administration of non-selective cannabinoids may delay the onset of cognitive deficits in AD patients; this will dramatically reduce the socio-economic burden of AD and improve the quality of life of the patients and their families.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284401/

Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain

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“A decline in neurogenesis in the hippocampus may underlie age-related memory impairment in rats and humans. We now show that WIN 55,212-2 administration for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid receptor stimulation therapy may thus provide clinical benefit for humans with age-associated memory impairment.”

“This report shows for the first time the potential therapeutic efficacy of endocannabinoid receptor stimulation in stimulating neurogenesis from proliferation to engraftment during normal aging in vivo. The current results, coupled with our previous observations regarding the role of endocannabinoid receptors, underscores the potential clinical benefits of cannabinoid pharmacotherapies during normal and pathological brain aging.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011092/

A cannabinoid mechanism in relapse to cocaine seeking.

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Abstract

“Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.”

http://www.ncbi.nlm.nih.gov/pubmed/11590440

Modulation Of The Endo-Cannabinoid System: Therapeutic Potential Against Cocaine Dependence

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 “Dependence on cocaine is still a main unresolved medical and social concern, and in spite of research efforts, no pharmacological therapy against cocaine dependence is yet available. Recent studies have shown that the endocannabinoid system participates in specific stages and aspects of drug dependence in general, and some of this evidence suggests an involvement of the cannabinoid system in cocaine effects. For example, cocaine administration has been shown to alter brain endocannabinoid levels, and the endocannabinoid system has been involved in long-term modifications of brain processes that might play a role in neuro/behavioral effects of psychostimulant drugs like cocaine. Human studies show that marijuana dependence is frequently associated with cocaine dependence, and that the cannabinoid receptor CNR1 gene polymorphism might be related to cocaine addiction. This article will review the main papers in the field showing how a modulation of different components of the cannabinoid system might interact with some of the neurobiological/behavioral effects of cocaine related to its reinforcing effects, evaluated in preclinical models or in clinical settings. The goal of this review will be to provide insights into the complex picture of cocaine abuse and addiction, and to extrapolate from such endocannabinoid-cocaine interactions useful information to test the therapeutic potential of cannabinoid ligands and endocannabinoid-level enhancers against cocaine dependence for future preclinical/clinical trials.”

“Summary and concluding remarks

Most of the scientific articles reviewed in the present manuscript have described studies of cannabinoid CB1 receptor agonists and antagonists tested against cocaine effects in preclinical models thought to be predictive of cocaine abuse. These studies have provided interesting results, especially for the ability of cannabinoid antagonists, and Rimonabant in particular, to significantly counteract some of the reinforcing actions of cocaine (104, 143). Collectively, the studies suggest that a cannabinoid tone, impaired by cannabinoid antagonist administration, is indeed involved in many of the reinforcing effects of cocaine which are believed to be responsible for cocaine abuse and addiction. On the other hand, there are no studies available showing interactions of drugs acting as cannabinoid levels modulators/enhancers on cocaine-induced behaviors. These drugs affecting directly the endogenous cannabinoid tone could interfere with cocaine effects in these preclinical procedures and could substantially increase our knowledge about the cannabinoid-neurobiology related to cocaine dependence.”

“Suggestions about possible genetic predisposition/vulnerability to cocaine dependence from human studies due to variants of the cannabinoid receptor CNR1 gene have given more strength to the link between endocannabinoids and cocaine. Due to the widespread distribution of cannabinoid receptors in the brain, and their abundance in brain areas playing pivotal roles in drug abuse and addiction, the different expression and regulation of cannabinoid receptors induced by genetic differences might be an important factor in the predisposition or vulnerability to drug dependence. For this reason, the potential to directly interact with endocannabinoid tone in selected brain areas, an effect that can be obtained with endocannabinoid uptake inhibitors or metabolism blockers (as shown also in genetically modified mice, 170), as compared to widespread actions of cannabinoid receptors agonists/antagonists, should be one of the next challenges in the research for medications able to counteract the abuse- and dependence-related behavioral/neurobiological effects of cocaine.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134985/

The genetic basis of the endocannabinoid system and drug addiction in humans.

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Abstract

“The cannabinoid receptor (CNR1) and the fatty acid amide hydrolase (FAAH) genes are located on chromosomes 6 and 1 in the 6q15 and 1p33 cytogenetic bands, respectively. CNR1 encodes a seven-transmembrane domain protein of 472 amino acids, whereas FAAH encodes one transmembrane domain of 579 amino acids. Several mutations found in these genes lead to altered mRNA stability and transcription rate or a reduction of the activity of the encoded protein. Increasing evidence shows that these functional mutations are related to dependence upon cocaine, alcohol, marijuana, heroin, nicotine and other drugs. One of the most compelling associations is with the C385A single nucleotide polymorphism (SNP), which is found in the FAAH gene. For all of the genetic polymorphisms reviewed here, it is difficult to form overall conclusions due to the high diversity of population samples being studied, ethnicity, the use of volunteers, heterogeneity of the recruitment criteria and the drug addiction phenotype studied. Care should be taken when generalizing the results from different studies. However, many works have repeatedly associated polymorphisms in the CNR1 and FAAH genes with drug-related behaviours; this suggests that these genes should be examined in further genetic studies focusing on drug addiction and other psychiatric disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/21937688

Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction.

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Abstract

“Substantial evidence suggests that all commonly abused drugs act upon the brain reward circuitry to ultimately increase extracellular concentrations of the neurotransmitter dopamine in the nucleus accumbens and other forebrain areas. Many drugs of abuse appear to increase dopamine levels by dramatically increase the firing and bursting rates of dopamine neurons located in the ventral mesencephalon. Recent clinical evidence in humans and behavioral evidence in animals indicate that cannabinoid receptor antagonists such as SR141716A (Rimonabant) can reduce the self-administration of, and craving for, several commonly addictive drugs. However, the mechanism of this potentially beneficial effect has not yet been identified. We propose, on the basis of recent studies in our laboratory and others, that these antagonists may act by blocking the effects of endogenously released cannabinoid molecules (endocannabinoids) that are released in an activity- and calcium-dependent manner from mesencephalic dopamine neurons. It is hypothesized that, through the antagonism of cannabinoid CB1 receptors located on inhibitory and excitatory axon terminals targeting the midbrain dopamine neurons, the effects of the endocannabinoids are occluded. The data from these studies therefore suggest that the endocannabinoid system and the CB1 receptors located in the ventral mesencephalon may play an important role in regulating drug reward processes, and that this substrate is recruited whenever dopamine neuron activity is increased.”

http://www.ncbi.nlm.nih.gov/pubmed/15878779

Treatment of Tourette Syndrome with Delta-9-Tetrahydrocannabinol (9-THC): No Influence on Neuropsychological Performance

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“Previous studies provide evidence that marijuana (Cannabis sativa) and delta-9-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive ingredient of marijuana, respectively, are effective in the treatment of tics and behavioral problems in Tourette syndrome (TS). It, therefore, has been speculated that the central cannabinoid receptor system might be involved in TS pathology. However, in healthy marijuana users there is an ongoing debate as to whether the use of cannabis causes acute and/or long-term cognitive deficits. In this randomized double-blind placebo-controlled study, we investigated the effect of a treatment with up to 10 mg Delta(9)-THC over a 6-week period on neuropsychological performance in 24 patients suffering from TS. During medication and immediately as well as 5-6 weeks after withdrawal of Delta(9)-THC treatment, no detrimental effect was seen on learning curve, interference, recall and recognition of word lists, immediate visual memory span, and divided attention. Measuring immediate verbal memory span, we even found a trend towards a significant improvement during and after treatment. Results from this study corroborate previous data suggesting that in patients suffering from TS, treatment with Delta(9)-THC causes neither acute nor long-term cognitive deficits. Larger and longer-duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS.”

“Anecdotal reports and two controlled studies provide evidence that marijuana (Cannabis sativa) and delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of marijuana, respectively, are effective in the treatment of tics and behavioral problems in TS.”

“In conclusion, our data are in agreement with anecdotal reports and a pilot study suggesting that -THC treatment in patients suffering from TS has no detrimental effect on neuropsychological performance. We hypothesize that the effects of -THC on cognition in TS patients might be different from those in healthy marijuana users because of the pathology of the disease. Since there is evidence that tics can be improved by THC, an involvement of the central CB1 receptor system in TS pathology has been suggested. However, larger and longer-duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS.”

http://www.nature.com/npp/journal/v28/n2/full/1300047a.html